222 results on '"Andreas Meinhardt"'
Search Results
2. The regional distribution of resident immune cells shapes distinct immunological environments along the murine epididymis
- Author
-
Christiane Pleuger, Dingding Ai, Minea L Hoppe, Laura T Winter, Daniel Bohnert, Dominik Karl, Stefan Guenther, Slava Epelman, Crystal Kantores, Monika Fijak, Sarina Ravens, Ralf Middendorff, Johannes U Mayer, Kate L Loveland, Mark Hedger, Sudhanshu Bhushan, and Andreas Meinhardt
- Subjects
epididymis ,epididymitis ,resident immune cells ,macrophages ,bacterial infection ,scRNASeq ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The epididymis functions as transition zone for post-testicular sperm maturation and storage and faces contrasting immunological challenges, i.e. tolerance towards spermatozoa vs. reactivity against pathogens. Thus, normal organ function and integrity relies heavily on a tightly controlled immune balance. Previous studies described inflammation-associated tissue damage solely in the distal regions (corpus, cauda), but not in the proximal regions (initial segment, caput). To understand the observed region-specific immunity along the epididymal duct, we have used an acute bacterial epididymitis mouse model and analyzed the disease progression. Whole transcriptome analysis using RNAseq 10 days post infection showed a pro-inflammatory environment within the cauda, while the caput exhibited only minor transcriptional changes. High-dimensional flow cytometry analyses revealed drastic changes in the immune cell composition upon infection with uropathogenic Escherichia coli. A massive influx of neutrophils and monocytes was observed exclusively in distal regions and was associated with bacterial appearance and tissue alterations. In order to clarify the reasons for the region-specific differences in the intensity of immune responses, we investigated the heterogeneity of resident immune cell populations under physiological conditions by scRNASeq analysis of extravascular CD45+ cells. Twelve distinct immune cell subsets were identified, displaying substantial differences in distribution along the epididymis as further assessed by flow cytometry and immunofluorescence staining. Macrophages constituted the majority of resident immune cells and were further separated in distinct subgroups based on their transcriptional profile, tissue location and monocyte-dependence. Crucially, the proximal and distal regions showed striking differences in their immunological landscapes. These findings indicate that resident immune cells are strategically positioned along the epididymal duct, potentially providing different immunological environments required for addressing the contrasting immunological challenges and thus, preserving tissue integrity and organ function.
- Published
- 2022
- Full Text
- View/download PDF
3. High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study
- Author
-
Maria Schroeder, Berfin Schaumburg, Zacharias Mueller, Ann Parplys, Dominik Jarczak, Kevin Roedl, Axel Nierhaus, Geraldine de Heer, Joern Grensemann, Bettina Schneider, Fabian Stoll, Tian Bai, Henning Jacobsen, Martin Zickler, Stephanie Stanelle-Bertram, Kristin Klaetschke, Thomas Renné, Andreas Meinhardt, Jens Aberle, Jens Hiller, Sven Peine, Lothar Kreienbrock, Karin Klingel, Stefan Kluge, and Guelsah Gabriel
- Subjects
SARS-CoV-2 ,COVID-19 ,sex differences ,sex hormones ,cytokines ,critical illness ,Infectious and parasitic diseases ,RC109-216 ,Microbiology ,QR1-502 - Abstract
Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.
- Published
- 2021
- Full Text
- View/download PDF
4. Mechanism of Inflammatory Associated Impairment of Sperm Function, Spermatogenesis and Steroidogenesis
- Author
-
Hiba Hasan, Sudhanshu Bhushan, Monika Fijak, and Andreas Meinhardt
- Subjects
testicular infection ,testicular inflammation ,autoimmunity ,paracrine regulation ,oxidative stress ,ROS ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Infection and inflammation are relevant entities of male reproductive disorders that can lead to sub-/infertility. Associated damage of the testis of affected men and in rodent models include leukocytic infiltration, edema formation, fibrosis, germ cell loss and reduced androgen levels. Negative effects on spermatogenesis are thought to be elicited by oxidative stress sustained mostly by increased levels of ROS and pro-inflammatory cytokines. Under normal conditions these cytokines have physiological functions. However, increased levels as seen in inflammation and infection, but also in obesity and cancer are harmful for germ cells and impair steroidogenesis. As a summary, there is mounting evidence that the activation of inflammatory pathways is a rather common feature in various forms of male testicular disorders that extends beyond established infectious/inflammatory cues. This mini review will focus on relevant entities and the mechanisms of how a dysbalance of local testicular factors contributes to disturbances of spermatogenesis and steroidogenesis.
- Published
- 2022
- Full Text
- View/download PDF
5. Corticosterone Enhances the AMPK-Mediated Immunosuppressive Phenotype of Testicular Macrophages During Uropathogenic Escherichia coli Induced Orchitis
- Author
-
Zhengguo Zhang, Ziming Jiang, Yiming Zhang, Yu Zhang, Yan Yan, Sudhanshu Bhushan, Andreas Meinhardt, Zhihai Qin, and Ming Wang
- Subjects
Corticosterone ,Testicular macrophage ,AMPK ,Fatty acid oxidation (FAO) ,Orchitis ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Testicular macrophages (TM) play a central role in maintaining testicular immune privilege and protecting spermatogenesis. Recent studies showed that their immunosuppressive properties are maintained by corticosterone in the testicular interstitial fluid, but the underlying molecular mechanisms are unknown. In this study, we treated mouse bone marrow-derived macrophages (BMDM) with corticosterone (50 ng/ml) and uncovered AMP-activated protein kinase (AMPK) activation as a critical event in M2 polarization at the phenotypic, metabolic, and cytokine production level. Primary TM exhibited remarkably similar metabolic and phenotypic features to corticosterone-treated BMDM, which were partially reversed by AMPK-inhibition. In a murine model of uropathogenic E. coli-elicited orchitis, intraperitoneal injection with corticosterone (0.1mg/day) increased the percentage of M2 TM in vivo, in a partially AMPK-dependent manner. This study integrates the influence of corticosterone on M2 macrophage metabolic pathways, phenotype, and function, and highlights a promising new avenue for the development of innovative therapeutics for orchitis patients.
- Published
- 2020
- Full Text
- View/download PDF
6. Differential Immune Response to Infection and Acute Inflammation Along the Epididymis
- Author
-
Christiane Pleuger, Erick José Ramo Silva, Adrian Pilatz, Sudhanshu Bhushan, and Andreas Meinhardt
- Subjects
epididymis ,epididymitis ,mononuclear phagocytes ,uropathogenic E. coli ,infertility ,bacterial infection ,Immunologic diseases. Allergy ,RC581-607 - Abstract
The epididymis is a tubular structure connecting the vas deferens to the testis. This organ consists of three main regions—caput, corpus, and cauda—that face opposing immunological tasks. A means of combating invading pathogens is required in the distally located cauda, where there is a risk of ascending bacterial infections originating from the urethra. Meanwhile, immune tolerance is necessary at the caput, where spermatozoa with immunogenic neo-antigens originate from the testis. Consistently, when challenged with live bacteria or inflammatory stimuli, the cauda elicits a much stronger immune response and inflammatory-inflicted damage than the caput. At the cellular level, a role for diverse and strategically positioned mononuclear phagocytes is emerging. At the mechanistic level, differential expression of immunoprotective and immunomodulatory mediators has been detected between the three main regions of the epididymis. In this review, we summarize the current state of knowledge about region-specific immunological characteristics and unveil possible underlying mechanisms on cellular and molecular levels. Improved understanding of the different immunological microenvironments is the basis for an improved therapy and counseling of patients with epididymal infections.
- Published
- 2020
- Full Text
- View/download PDF
7. Immune Cell Subtypes and Their Function in the Testis
- Author
-
Sudhanshu Bhushan, María S. Theas, Vanesa A. Guazzone, Patricia Jacobo, Ming Wang, Monika Fijak, Andreas Meinhardt, and Livia Lustig
- Subjects
testis ,immune privilege ,macrophages ,dendritic cells ,T lymphocytes ,mast cells ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Immunoregulation in the testis is characterized by a balance between immuno-suppression (or immune privilege) and the ability to react to infections and inflammation. In this review, we analyze the phenotypes of the various immune cell subtypes present in the testis, and how their functions change between homeostatic and inflammatory conditions. Starting with testicular macrophages, we explore how this heterogeneous population is shaped by the testicular microenvironment to ensure immune privilege. We then describe how dendritic cells exhibit a tolerogenic status under normal conditions, but proliferate, mature and then stimulate effector T-cell expansion under inflammatory conditions. Finally, we outline the two T-cell populations in the testis: CD4+/CD8+ αβ T cells and CD4+/CD8+ Foxp3+ regulatory T cells and describe the distribution and function of mast cells. All these cells help modulate innate immunity and regulate the immune response. By improving our understanding of immune cell behavior in the testis under normal and inflammatory conditions, we will be better placed to evaluate testis impairment due to immune mechanisms in affected patients.
- Published
- 2020
- Full Text
- View/download PDF
8. Pathomechanisms of Autoimmune Based Testicular Inflammation
- Author
-
Livia Lustig, Vanesa A. Guazzone, María S. Theas, Christiane Pleuger, Patricia Jacobo, Cecilia V. Pérez, Andreas Meinhardt, and Monika Fijak
- Subjects
testicular inflammation ,autoimmunity ,experimental autoimmune orchitis (EAO) ,infertility ,testis immunoregulation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Infection and inflammation of the male reproductive tract are relevant causes of infertility. Inflammatory damage occurs in the special immunosuppressive microenvironment of the testis, a hallmark termed testicular immune privilege, which allows tolerance to neo-antigens from developing germ cells appearing at puberty, long after the establishment of systemic immune tolerance. Experimental autoimmune orchitis (EAO) is a well-established rodent model of chronic testicular inflammation and organ specific autoimmunity that offers a valuable in vivo tool to investigate the pathological and molecular mechanisms leading to the breakdown of the testicular immune privilege. The disease is characterized by the infiltration of the interstitium by immune cells (mainly macrophages, dendritic cells, and T cells), formation of autoantibodies against testicular antigens, production of pro-inflammatory mediators such as NO, MCP1, TNFα, IL6, or activins and dysregulation of steroidogenesis with reduced levels of serum testosterone. EAO leads to sloughing of germ cells, atrophic seminiferous tubules and fibrotic remodeling, parameters all found similarly to changes in human biopsies from infertile patients with inflammatory infiltrates. Interestingly, testosterone supplementation during the course of EAO leads to expansion of the regulatory T cell population and inhibition of disease development. Knowledge of EAO pathogenesis aims to contribute to a better understanding of human testicular autoimmune disease as an essential prerequisite for improved diagnosis and treatment.
- Published
- 2020
- Full Text
- View/download PDF
9. Epididymitis: revelations at the convergence of clinical and basic sciences
- Author
-
Vera Michel, Adrian Pilatz, Mark P Hedger, and Andreas Meinhardt
- Subjects
acute epididymitis ,animal models of bacterial epididymitis ,epididymal duct ,epididymal immune environment ,fertility ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Acute epididymitis represents a common medical condition in the urological outpatient clinic. Mostly, epididymitis is caused by bacterial ascent through the urogenital tract, with pathogens originating either from sexually transmitted diseases or urinary tract infections. Although conservative antimicrobial therapy is possible in the majority of patients and is usually sufficient to eradicate the pathogen, studies have shown persistent oligozoospermia and azoospermia in up to 40% of these patients. Animal models of epididymitis are created to delineate the underlying reasons for this observation and the additional impairment of sperm function that is often associated with the disease. Accumulated data provide evidence of a differential expression of immune cells, immunoregulatory genes and pathogen-sensing molecules along the length of the epididymal duct. The evidence suggests that a tolerogenic environment exists in the caput epididymidis, but that inflammatory responses are most intense toward the cauda epididymidis. This is consistent with the need to provide protection for the neo-antigens of spermatozoa emerging from the testis, without compromising the ability to respond to ascending infections. However, severe inflammatory responses, particularly in the cauda, may lead to collateral damage to the structure and function of the epididymis. Convergence of the clinical observations with appropriate animal studies should lead to better understanding of the immunological environment throughout the epididymis, the parameters underlying susceptibility to epididymitis, and to therapeutic approaches that can mitigate epididymal damage and subsequent fertility problems.
- Published
- 2015
- Full Text
- View/download PDF
10. H3K79 methylation: a new conserved mark that accompanies H4 hyperacetylation prior to histone-to-protamine transition in Drosophila and rat
- Author
-
Christine Dottermusch-Heidel, Stefanie M. K. Gärtner, Isabel Tegeder, Christina Rathke, Bridlin Barckmann, Marek Bartkuhn, Sudhanshu Bhushan, Klaus Steger, Andreas Meinhardt, and Renate Renkawitz-Pohl
- Subjects
Gpp ,Grappa ,Gpp-D ,Spermiogenesis ,Histone-to-protamine transition ,H4 acetylation ,Science ,Biology (General) ,QH301-705.5 - Abstract
During spermiogenesis, haploid spermatids undergo extensive chromatin remodeling events in which histones are successively replaced by more basic protamines to generate highly compacted chromatin. Here we show for the first time that H3K79 methylation is a conserved feature preceding the histone-to-protamine transition in Drosophila melanogaster and rat. During Drosophila spermatogenesis, the Dot1-like methyltransferase Grappa (Gpp) is primarily expressed in canoe stage nuclei. The corresponding H3K79 methylation is a histone modification that precedes the histone-to-protamine transition and correlates with histone H4 hyperacetylation. When acetylation was inhibited in cultured Drosophila testes, nuclei were smaller and chromatin was compact, Gpp was little synthesized, H3K79 methylation was strongly reduced, and protamines were not synthesized. The Gpp isoform Gpp-D has a unique C-terminus, and Gpp is essential for full fertility. In rat, H3K79 methylation also correlates with H4 hyperacetylation but not with active RNA polymerase II, which might point towards a conserved function in chromatin remodeling during the histone-to-protamine transition in both Drosophila and rat.
- Published
- 2014
- Full Text
- View/download PDF
11. Necrosis is the dominant cell death pathway in uropathogenic Escherichia coli elicited epididymo-orchitis and is responsible for damage of rat testis.
- Author
-
Yongning Lu, Sudhanshu Bhushan, Svetlin Tchatalbachev, Marcelo Marconi, Martin Bergmann, Wolfgang Weidner, Trinad Chakraborty, and Andreas Meinhardt
- Subjects
Medicine ,Science - Abstract
Male infertility is a frequent medical condition, compromising approximately one in twenty men, with infections of the reproductive tract constituting a major etiological factor. Bacterial epididymo-orchitis results in acute inflammation most often caused by ascending canalicular infections from the urethra via the continuous male excurrent ductal system. Uropathogenic Escherichia coli (UPEC) represent a relevant pathogen in urogenital tract infections. To explore how bacteria can cause damage and cell loss and thus impair fertility, an in vivo epididymo-orchitis model was employed in rats by injecting UPEC strain CFT073 into the vas deference in close proximity to the epididymis. Seven days post infection bacteria were found predominantly in the testicular interstitial space. UPEC infection resulted in severe impairment of spermatogenesis by germ cell loss, damage of testicular somatic cells, a decrease in sperm numbers and a significant increase in TUNEL (+) cells. Activation of caspase-8 (extrinsic apoptotic pathway), caspase-3/-6 (intrinsic apoptotic pathway), caspase-1 (pyroptosis pathway) and the presence of 180 bp DNA fragments, all of which serve as indicators of the classical apoptotic pathway, were not observed in infected testis. Notably, electron microscopical examination revealed degenerative features of Sertoli cells (SC) in UPEC infected testis. Furthermore, the passive release of high mobility group protein B1 (HMGB1), as an indication of necrosis, was observed in vivo in infected testis. Thus, necrosis appears to be the dominant cell death pathway in UPEC infected testis. Substantial necrotic changes seen in Sertoli cells will contribute to impaired spermatogenesis by loss of function in supporting the dependent germ cells.
- Published
- 2013
- Full Text
- View/download PDF
12. Uropathogenic E. coli induce different immune response in testicular and peritoneal macrophages: implications for testicular immune privilege.
- Author
-
Sudhanshu Bhushan, Hamid Hossain, Yongning Lu, Andreas Geisler, Svetlin Tchatalbachev, Zbigniew Mikulski, Gerhard Schuler, Jörg Klug, Adrian Pilatz, Florian Wagenlehner, Trinad Chakraborty, and Andreas Meinhardt
- Subjects
Medicine ,Science - Abstract
Infertility affects one in seven couples and ascending bacterial infections of the male genitourinary tract by Escherichia coli are an important cause of male factor infertility. Thus understanding mechanisms by which immunocompetent cells such as testicular macrophages (TM) respond to infection and how bacterial pathogens manipulate defense pathways is of importance. Whole genome expression profiling of TM and peritoneal macrophages (PM) infected with uropathogenic E. coli (UPEC) revealed major differences in regulated genes. However, a multitude of genes implicated in calcium signaling pathways was a common feature which indicated a role of calcium-dependent nuclear factor of activated T cells (NFAT) signaling. UPEC-dependent NFAT activation was confirmed in both cultured TM and in TM in an in vivo UPEC infectious rat orchitis model. Elevated expression of NFATC2-regulated anti-inflammatory cytokines was found in TM (IL-4, IL-13) and PM (IL-3, IL-4, IL-13). NFATC2 is activated by rapid influx of calcium, an activity delineated to the pore forming toxin alpha-hemolysin by bacterial mutant analysis. Alpha-hemolysin suppressed IL-6 and TNF-α cytokine release from PM and caused differential activation of MAP kinase and AP-1 signaling pathways in TM and PM leading to reciprocal expression of key pro-inflammatory cytokines in PM (IL-1α, IL-1β, IL-6 downregulated) and TM (IL-1β, IL-6 upregulated). In addition, unlike PM, LPS-treated TM were refractory to NFκB activation shown by the absence of degradation of IκBα and lack of pro-inflammatory cytokine secretion (IL-6, TNF-α). Taken together, these results suggest a mechanism to the conundrum by which TM initiate immune responses to bacteria, while maintaining testicular immune privilege with its ability to tolerate neo-autoantigens expressed on developing spermatogenic cells.
- Published
- 2011
- Full Text
- View/download PDF
13. Standards in semen examination: publishing reproducible and reliable data based on high-quality methodology
- Author
-
Lars Björndahl, Christopher L R Barratt, David Mortimer, Ashok Agarwal, Robert J Aitken, Juan G Alvarez, Natalie Aneck-Hahn, Stefan Arver, Elisabetta Baldi, Lluís Bassas, Florence Boitrelle, Riana Bornman, Douglas T Carrell, José A Castilla, Gerardo Cerezo Parra, Jerome H Check, Patricia S Cuasnicu, Sally Perreault Darney, Christiaan de Jager, Christopher J De Jonge, Joël R Drevet, Erma Z Drobnis, Stefan S Du Plessis, Michael L Eisenberg, Sandro C Esteves, Evangelini A Evgeni, Alberto Ferlin, Nicolas Garrido, Aleksander Giwercman, Ilse G F Goovaerts, Trine B Haugen, Ralf Henkel, Lars Henningsohn, Marie-Claude Hofmann, James M Hotaling, Piotr Jedrzejczak, Pierre Jouannet, Niels Jørgensen, Jackson C Kirkman Brown, Csilla Krausz, Maciej Kurpisz, Ulrik Kvist, Dolores J Lamb, Hagai Levine, Kate L Loveland, Robert I McLachlan, Ali Mahran, Liana Maree, Sarah Martins da Silva, Michael T Mbizvo, Andreas Meinhardt, Roelof Menkveld, Sharon T Mortimer, Sergey Moskovtsev, Charles H Muller, Maria José Munuce, Monica Muratori, Craig Niederberger, Cristian O’Flaherty, Rafael Oliva, Willem Ombelet, Allan A Pacey, Michael A Palladino, Ranjith Ramasamy, Liliana Ramos, Nathalie Rives, Eduardo Rs Roldan, Susan Rothmann, Denny Sakkas, Andrea Salonia, Maria Cristina Sánchez-Pozo, Rosanna Sapiro, Stefan Schlatt, Peter N Schlegel, Hans-Christian Schuppe, Rupin Shah, Niels E Skakkebæk, Katja Teerds, Igor Toskin, Herman Tournaye, Paul J Turek, Gerhard van der Horst, Monica Vazquez-Levin, Christina Wang, Alex Wetzels, Theodosia Zeginiadou, Armand Zini, Faculty of Medicine and Pharmacy, Clinical sciences, Biology of the Testis, Centre for Reproductive Medicine - Gynaecology, Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Rouen, Normandie Université (NU), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Neuroendocrine, Endocrine and Germinal Differentiation Communication (NorDic), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Björndahl, L, Barratt, Clr, Mortimer, D, Agarwal, A, Aitken, Rj, Alvarez, Jg, Aneck-Hahn, N, Arver, S, Baldi, E, Bassas, L, Boitrelle, F, Bornman, R, Carrell, Dt, Castilla, Ja, Cerezo Parra, G, Check, Jh, Cuasnicu, P, Darney, Sp, de Jager, C, De Jonge, Cj, Drevet, Jr, Drobnis, Ez, Du Plessis, S, Eisenberg, Ml, Esteves, Sc, Evgeni, Ea, Ferlin, A, Garrido, N, Giwercman, A, Goovaerts, Igf, Haugen, Tb, Henkel, R, Henningsohn, L, Hofmann, Mc, Hotaling, Jm, Jedrzejczak, P, Jouannet, P, Jørgensen, N, Kirkman Brown, Jc, Krausz, C, Kurpisz, M, Kvist, U, Lamb, Dj, Levine, H, Loveland, Kl, Mclachlan, Ri, Mahran, A, Maree, L, Martins da Silva, S, Mbizvo, Mt, Meinhardt, A, Menkveld, R, Mortimer, St, Moskovtsev, S, Muller, Ch, Munuce, Mj, Muratori, M, Niederberger, C, O'Flaherty, C, Oliva, R, Ombelet, W, Pacey, Aa, Palladino, Ma, Ramasamy, R, Ramos, L, Rives, N, Roldan, Er, Rothmann, S, Sakkas, D, Salonia, A, Sánchez-Pozo, Mc, Sapiro, R, Schlatt, S, Schlegel, Pn, Schuppe, Hc, Shah, R, Skakkebæk, Ne, Teerds, K, Toskin, I, Tournaye, H, Turek, Pj, van der Horst, G, Vazquez-Levin, M, Wang, C, Wetzels, A, Zeginiadou, T, Zini, A., Pacey, Allan/0000-0002-4387-8871, Arver, Stefan/0000-0002-2925-355X, Mortimer, David/0000-0002-0638-2893, Barratt, christopher/0000-0003-0062-9979, Kirkman-Brown, Jackson, C/0000-0003-2833-8970, Bjorndahl, Lars/0000-0002-4709-5807, Baldi, Elisabetta/0000-0003-1808-3097, Aitken, Robert John/0000-0002-9152-156X, Bjorndahl, Lars, Barratt, Christopher L. R., Mortimer, David, Agarwal, Ashok, Aitken, Robert J., Alvarez, Juan G., Aneck-Hahn, Natalie, Arver, Stefan, Baldi, Elisabetta, Bassas, Lluis, Boitrelle, Florence, Bornman, Riana, Carrell, Douglas T., Castilla, Jose A., Cerezo Parra, Gerardo, Check, Jerome H., Cuasnicu, Patricia S., Darney, Sally Perreault, de Jager, Christiaan, De Jonge, Christopher J., Drevet, Joel R., Drobnis, Erma Z., Du Plessis, Stefan S., Eisenberg, Michael L., Esteves, Sandro C., Evgeni, Evangelini A., Ferlin, Alberto, Garrido, Nicolas, Giwercman, Aleksander, Goovaerts, Ilse G. F., Haugen, Trine B., Henkel, Ralf, Henningsohn, Lars, Hofmann, Marie-Claude, Hotaling, James M., Jedrzejczak, Piotr, Jouannet, Pierre, Jorgensen, Niels, Brown, Jackson C. Kirkman, Krausz, Csilla, Kurpisz, Maciej, Kvist, Ulrik, Lamb, Dolores J., Levine, Hagai, Loveland, Kate L., McLachlan, Robert, I, Mahran, Ali, Maree, Liana, da Silva, Sarah Martins, Mbizvo, Michael T., Meinhardt, Andreas, Menkveld, Roelof, Mortimer, Sharon T., Moskovtsev, Sergey, Muller, Charles H., Jose Munuce, Maria, Muratori, Monica, Niederberger, Craig, O'Flaherty, Cristian, Oliva, Rafael, OMBELET, Willem, Pacey, Allan A., Palladino, Michael A., Ramasamy, Ranjith, Ramos, Liliana, Rives, Nathalie, Roldan, Eduardo Rs, Rothmann, Susan, Sakkas, Denny, Salonia, Andrea, Cristina Sanchez-Pozo, Maria, Sapiro, Rosanna, Schlatt, Stefan, Schlegel, Peter N., Schuppe, Hans-Christian, Shah, Rupin, Skakkebaek, Niels E., Teerds, Katja, Toskin, Igor, Tournaye, Herman, Turek, Paul J., van der Horst, Gerhard, Vazquez-Levin, Monica, Wang, Christina, Wetzels, Alex, Zeginiadou, Theodosia, and Zini, Armand
- Subjects
Reproducitibility ,[SDV]Life Sciences [q-bio] ,andrology ,basic semen examination ,journal requirements ,laboratory training ,patient security ,quality control ,reproducibility ,reproductive medicine ,science development ,standardized laboratory procedures ,Humans ,Reproducibility of Results ,Publishing ,Semen ,Semen Analysis ,Andrology ,Obstetrics & Reproductive Medicine ,Biology ,11 Medical and Health Sciences ,Reproductive Biology ,Science & Technology ,Rehabilitation ,Obstetrics & Gynecology ,Obstetrics and Gynecology ,Reproductive Medicine ,16 Studies in Human Society ,Human and Animal Physiology ,Fysiologie van Mens en Dier ,Human medicine ,Life Sciences & Biomedicine - Abstract
Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.
- Published
- 2022
14. Supplementary Figure 3 from MIF Produced by Bone Marrow–Derived Macrophages Contributes to Teratoma Progression after Embryonic Stem Cell Transplantation
- Author
-
Yi Ren, Richard Bucala, Wise Young, Andreas Meinhardt, Shusen Zheng, Dongming Sun, Li Liang, Tianyi Li, Iman Tadmori, Mingmei Wu, Changshun Shao, Xijing Zhang, Zhaoxia Duan, Kai Cao, Jianqing Fan, Lin Leng, Tianxiang Chen, and Xi Wang
- Abstract
PDF file - 450K, MIF contributes to teratoma growth
- Published
- 2023
15. Supplementary Figure 2 from MIF Produced by Bone Marrow–Derived Macrophages Contributes to Teratoma Progression after Embryonic Stem Cell Transplantation
- Author
-
Yi Ren, Richard Bucala, Wise Young, Andreas Meinhardt, Shusen Zheng, Dongming Sun, Li Liang, Tianyi Li, Iman Tadmori, Mingmei Wu, Changshun Shao, Xijing Zhang, Zhaoxia Duan, Kai Cao, Jianqing Fan, Lin Leng, Tianxiang Chen, and Xi Wang
- Abstract
PDF file - 100K, ESCs recruit bone marrow-derived macrophages
- Published
- 2023
16. Supplementary Figure 1 from MIF Produced by Bone Marrow–Derived Macrophages Contributes to Teratoma Progression after Embryonic Stem Cell Transplantation
- Author
-
Yi Ren, Richard Bucala, Wise Young, Andreas Meinhardt, Shusen Zheng, Dongming Sun, Li Liang, Tianyi Li, Iman Tadmori, Mingmei Wu, Changshun Shao, Xijing Zhang, Zhaoxia Duan, Kai Cao, Jianqing Fan, Lin Leng, Tianxiang Chen, and Xi Wang
- Abstract
PDF file - 103K, Deletion of MIF from the host inhibits teratoma development
- Published
- 2023
17. Supplementary Methods from MIF Produced by Bone Marrow–Derived Macrophages Contributes to Teratoma Progression after Embryonic Stem Cell Transplantation
- Author
-
Yi Ren, Richard Bucala, Wise Young, Andreas Meinhardt, Shusen Zheng, Dongming Sun, Li Liang, Tianyi Li, Iman Tadmori, Mingmei Wu, Changshun Shao, Xijing Zhang, Zhaoxia Duan, Kai Cao, Jianqing Fan, Lin Leng, Tianxiang Chen, and Xi Wang
- Abstract
PDF file - 103K
- Published
- 2023
18. Testicular macrophages: development and function in health and disease
- Author
-
Sudhanshu Bhushan, Andreas Meinhardt, Nathalie Dejucq-Rainsford, Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Deutsche Forschungsgemeinschaft, DFG: BH 93/1-4, GRK 1871/2, and Chard-Hutchinson, Xavier
- Subjects
Male ,Mammals ,education.field_of_study ,Macrophages ,[SDV]Life Sciences [q-bio] ,Immunology ,Cell ,Population ,Disease ,Biology ,medicine.disease ,Phenotype ,Virus ,Male infertility ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Immune system ,Testis ,medicine ,Animals ,Humans ,Immunology and Allergy ,education ,Function (biology) - Abstract
International audience; Macrophages comprise a heterogeneous immune cell population and display niche-specific phenotypes and functions in almost all organs. Testicular macrophages (TMs) perform essential immune and non-immune functions in the mammalian male gonads. Here, we discuss the most recent findings on TM ontogeny, heterogeneity, and function under steady state and inflammatory conditions. We also highlight new discoveries regarding the functions of macrophages during bacterial and viral infections of the testes and how macrophages may indirectly help the establishment of a reservoir through virus seeding. Understanding TM function and macrophage-related mechanisms of disease might assist in developing new opportunities for intervention in male infertility. © 2021 Elsevier Ltd
- Published
- 2022
19. Activin A and CCR2 regulate macrophage function in testicular fibrosis caused by experimental autoimmune orchitis
- Author
-
Wei Peng, Artem Kepsch, Till O. Kracht, Hiba Hasan, Rukmali Wijayarathna, Eva Wahle, Christiane Pleuger, Sudhanshu Bhushan, Stefan Günther, A. Christine Kauerhof, Ana Planinić, Daniela Fietz, Hans-Christian Schuppe, Małgorzata Wygrecka, Kate L. Loveland, Davor Ježek, Andreas Meinhardt, Mark P. Hedger, and Monika Fijak
- Subjects
Inflammation ,Male ,Pharmacology ,Follistatin ,Receptors, CCR2 ,Macrophages ,Orchitis ,Cell Biology ,Fibrosis ,Fibronectins ,Mice ,Receptors, CCR2 / genetics ,Cellular and Molecular Neuroscience ,Animals ,Humans ,Molecular Medicine ,Activin A ,CCR2 ,CXCR4 ,EAO ,MMP2 ,Testicular inflammation ,Molecular Biology - Abstract
Experimental autoimmune-orchitis (EAO), a rodent model of chronic testicular inflammation and fibrosis, replicates pathogenic changes seen in some cases of human spermatogenic disturbances. During EAO, increased levels of pro-inflammatory and pro-fibrotic mediators such as TNF, CCL2, and activin A are accompanied by infiltration of leukocytes into the testicular parenchyma. Activin A levels correlate with EAO severity, while elevated CCL2 acting through its receptor CCR2 mediates leukocyte trafficking and recruits macrophages. CCR2 + CXCR4 + macrophages producing extracellular matrix proteins contribute widely to fibrogenesis. Furthermore, testicular macrophages (TMs) play a critical role in organ homeostasis. Therefore, we aimed to investigate the role of the activin A/CCL2-CCR2/macrophage axis in the development of testicular fibrosis. Following EAO induction, we observed lower levels of organ damage, collagen deposition, and leukocyte infiltration (including fibronectin+, collagen I+and CXCR4+TMs) inCcr2−/−mice than inWTmice. Furthermore, levels ofIl-10,Ccl2, and the activin A subunitInhbamRNAs were lower inCcr2−/−EAO testes. Notably, fibronectin+TMs were also present in biopsies from patients with impaired spermatogenesis and fibrotic alterations. Overexpression of the activin A antagonist follistatin reduced tissue damage and collagen I+TM accumulation inWTEAO testes, while treating macrophages with activin A in vitro increased the expression ofCcr2,Fn1,Cxcr4,andMmp2and enhanced migration along a CCL2 gradient; these effects were abolished by follistatin. Taken together, our data indicate that CCR2 and activin A promote fibrosis during testicular inflammation by regulating macrophage function. Inhibition of CCR2 or activin A protects against damage progression, offering a promising avenue for therapeutic intervention.
- Published
- 2022
20. Author response: The regional distribution of resident immune cells shapes distinct immunological environments along the murine epididymis
- Author
-
Christiane Pleuger, Dingding Ai, Minea L Hoppe, Laura T Winter, Daniel Bohnert, Dominik Karl, Stefan Guenther, Slava Epelman, Crystal Kantores, Monika Fijak, Sarina Ravens, Ralf Middendorff, Johannes U Mayer, Kate L Loveland, Mark Hedger, Sudhanshu Bhushan, and Andreas Meinhardt
- Published
- 2022
21. Targeted disruption of galectin 3 in mice delays the first wave of spermatogenesis and increases germ cell apoptosis
- Author
-
Tao Lei, Sandra M. Blois, Stefan A. Wudy, Fu-Tong Liu, Sudhanshu Bhushan, Andreas Meinhardt, Annie Chi-Chun Huang, Michaela F. Hartmann, Martin Bergmann, Monika Fijak, Hung-Lin Chen, Nancy Freitag, and Eva Wahle
- Subjects
Pharmacology ,endocrine system ,0303 health sciences ,Leydig cell ,Testicular atrophy ,urogenital system ,Somatic cell ,030302 biochemistry & molecular biology ,Cell Biology ,Steroid biosynthesis ,Biology ,Sertoli cell ,medicine.disease ,Cell biology ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,medicine.anatomical_structure ,Galectin-3 ,Apoptosis ,medicine ,Molecular Medicine ,Molecular Biology ,Germ cell - Abstract
Galectin 3 is a multifunctional lectin implicated in cellular proliferation, differentiation, adhesion, and apoptosis. This lectin is broadly expressed in testicular somatic cells and germ cells, and is upregulated during testicular development. Since the role of galectin 3 in testicular function remains elusive, we aimed to characterize the role of galectin 3 in testicular physiology. We found that galectin 3 transgenic mice (Lgals3-/-) exhibited significantly decreased testicular weight in adulthood compared to controls. The transgenic mice also exhibited a delay to the first wave of spermatogenesis, a decrease in the number of germ cells at postnatal day 5 (P5) and P15, and defective Sertoli cell maturation. Mechanistically, we found that Insulin-like-3 (a Leydig cell marker) and enzymes involved in steroid biosynthesis were significantly upregulated in adult Lgals3-/- testes. These observations were accompanied by increased serum testosterone levels. To determine the underlying causes of the testicular atrophy, we monitored cellular apoptosis. Indeed, adult Lgals3-/- testicular cells exhibited an elevated apoptosis rate that is likely driven by downregulated Bcl-2 and upregulated Bax and Bak expression, molecules responsible for live/death cell balance. Moreover, the percentage of testicular macrophages within CD45+ cells was decreased in Lgals3-/- mice. These data suggest that galectin 3 regulates spermatogenesis initiation and Sertoli cell maturation in part, by preventing germ cells from undergoing apoptosis and regulating testosterone biosynthesis. Going forward, understanding the role of galectin 3 in testicular physiology will add important insights into the factors governing the development of germ cells and steroidogenesis and delineate novel biomarkers of testicular function.
- Published
- 2021
22. High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study
- Author
-
Axel Nierhaus, Jens Hiller, Maria Schroeder, Thomas Renné, Bettina Schneider, Joern Grensemann, Sven Peine, Stefan Kluge, Dominik Jarczak, Martin Zickler, Fabian Stoll, Henning Jacobsen, Ann Parplys, Kristin Klaetschke, Jens Aberle, Andreas Meinhardt, Geraldine de Heer, Stephanie Stanelle-Bertram, Zacharias Mueller, Lothar Kreienbrock, Tian Bai, Guelsah Gabriel, Berfin Schaumburg, Kevin Roedl, and Karin Klingel
- Subjects
sex differences ,Male ,medicine.medical_specialty ,Critical Care ,Coronavirus disease 2019 (COVID-19) ,Epidemiology ,Critical Illness ,medicine.medical_treatment ,Immunology ,sex hormones ,Severity of Illness Index ,Microbiology ,Interferon-gamma ,Extracorporeal Membrane Oxygenation ,Risk Factors ,Virology ,Internal medicine ,Drug Discovery ,Severity of illness ,Extracorporeal membrane oxygenation ,medicine ,Humans ,Testosterone ,Sex Distribution ,Risk factor ,Aged ,Retrospective Studies ,Aged, 80 and over ,Estradiol ,SARS-CoV-2 ,business.industry ,Hypogonadism ,COVID-19 ,Testosterone (patch) ,Retrospective cohort study ,General Medicine ,Middle Aged ,cytokines ,Intensive Care Units ,Infectious Diseases ,Critical illness ,Original Article ,Female ,Parasitology ,business ,Research Article ,Hormone - Abstract
Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.
- Published
- 2021
23. Infektionen und Entzündungen der ableitenden Samenwege und akzessorischen Geschlechtsdrüsen
- Author
-
Hans-Christian Schuppe, Adrian Pilatz, Andreas Meinhardt, and Hermann M. Behre
- Published
- 2022
24. Regulation of macrophage number and gene transcript levels by activin A and its binding protein, follistatin, in the testes of adult mice
- Author
-
Sneha Biniwale, Rukmali Wijayarathna, Christiane Pleuger, Sudhanshu Bhushan, Kate L. Loveland, Andreas Meinhardt, and Mark P. Hedger
- Subjects
Male ,Follistatin ,Mice ,Reproductive Medicine ,Macrophages ,Immunology ,Testis ,Obstetrics and Gynecology ,Immunology and Allergy ,Animals ,Humans ,Carrier Proteins ,Activins - Abstract
The cytokine activin A is expressed throughout testicular development and is a critical regulator of macrophage function, but its effects on the testicular macrophages are not well-defined. Macrophage distribution and gene transcript levels were examined in testes of adult mice with reduced levels of either activin A (Inhba
- Published
- 2021
25. Examination of testicular lumicrine regulation of activins and immunoregulatory genes in the epididymal caput
- Author
-
Kate L Loveland, Andreas Meinhardt, Rosemary Genovese, Mark P. Hedger, Nigel P. Groome, Barry T. Hinton, and Rukmali Wijayarathna
- Subjects
Male ,endocrine system ,Urology ,Endocrinology, Diabetes and Metabolism ,Biology ,Andrology ,Mice ,Endocrinology ,Testis ,medicine ,Immune Tolerance ,Animals ,Inhibins ,Receptor ,Testosterone ,Epididymis ,urogenital system ,Efferent ducts ,Spermatozoa ,Epithelium ,Activins ,INHBB ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Reproductive Medicine ,Models, Animal ,Immunohistochemistry ,Ligation - Abstract
Background Immunoregulatory genes encoding activin A (Inhba) and B (Inhbb), and indolamine 2,3-dioxygenase-1 (Ido1) are highly expressed in the murine caput epididymidis, which also has a network of intraepithelial mononuclear phagocytes. This environment is postulated to promote immunological tolerance to epididymal sperm. The factors regulating the immunoregulatory agents in the epididymal caput are poorly understood. Objectives This study aimed to investigate the potential role of testicular lumicrine factors in regulating activin and other immune-related genes in the caput epididymidis. Materials and methods The efferent ducts in adult C57/Bl6 mice were exposed and ligated bilaterally. Serum and tissues were collected seven days later. Animals with bilateral sham ligation and animals with no ligations (collectively referred to as the "intact" group) were used as controls. Results Pressure-induced seminiferous epithelial damage due to intratubular fluid accumulation was observed in all ligated testes. Testicular inhibin was significantly increased and testosterone was elevated in some animals following bilateral ligation, but serum testosterone, serum LH, and serum inhibin were normal. Ligation caused epithelial regression in the initial segment, with similar but less severe effects in other caput segments. Activin A staining by immunohistochemistry in the epithelium was reduced in bilateral ligation, particularly in the initial segment, with moderately reduced staining intensity in the rest of the caput. Inhba expression within the caput was not significantly affected by bilateral ligation, but Inhbb was reduced by more than 60%. Transcripts encoding the macrophage-specific receptor Cx3cr1 were significantly reduced following bilateral ligation, but other immune cell markers, Ido1, and inflammatory genes were unaffected. Conclusion These data indicate that testicular lumicrine secretion regulates several genes that are preferentially expressed in the initial segment, but has marginal effects on genes such as those encoding activin A and IDO1, which are expressed more widely in the caput.
- Published
- 2021
26. Sex hormone dysregulations are associated with disease severity in critically ill male COVID-19 patients - a retrospective analysis
- Author
-
Tian Bai, Henning Jacobsen, Stefan Kluge, Bettina Schneider, Stephanie Stanelle-Bertram, Dominik Jarczak, Sven Peine, Joern Grensemann, Zacharias Mueller, Fabian Stoll, Karin Klingel, Axel Nierhaus, Jens Hiller, Thomas Renné, Ann Parplys, Kevin Roedl, Jens Aberle, Geraldine de Heer, Martin Zickler, Andreas Meinhardt, Lothar Kreienbrock, Maria Schroeder, Guelsah Gabriel, Kristin Klaetschke, and Berfin Schaumburg
- Subjects
medicine.medical_specialty ,Text mining ,Sex hormone-binding globulin ,Disease severity ,biology ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Critically ill ,Internal medicine ,biology.protein ,medicine ,Retrospective analysis ,business - Abstract
BACKGROUNDMale sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. We sought to characterize sex differences in hormone levels and cytokine responses in critically ill COVID-19 patients.METHODSWe performed a retrospective cohort study of critically ill COVID-19 patients. Males and females were compared. Multivariate regression was performed to assess the association between sex hormones, cytokine responses and the requirement for extracorporeal membrane oxygenation (ECMO) treatment.RESULTSWe analyzed sex hormone levels (estradiol and testosterone) of n=181 male and female individuals. These consisted of n=50 critically ill COVID-19 patients (n=39 males, n=11 females), n=42 critically ill non-COVID-19 patients (n=27 males, n=15 females), n=39 non-COVID-19 patients with coronary heart diseases (CHD) (n=25 males, n=14 females) and n=50 healthy individuals (n=30 males, n=20 females). We detected highest estradiol levels in critically ill male COVID-19 patients compared to non-COVID-19 patients (p=0.0123), patients with CHD (p=0.0002) or healthy individuals (p=0.0007). Lowest testosterone levels were detected in critically ill male COVID-19 patients compared to non-COVID-19 patients (p=0.0094), patients with CHD (p=0.0068) or healthy individuals (pp=0.0301; IL-1RA, p=0.0160; IL-6, p=0.0145; MCP-1, p=0.0052; MIP-1α, p=0.0134) were significantly elevated in those with higher Sequential Organ Failure Assessment (SOFA) scores (8-11). Linear regression analysis revealed that herein IFN-γ levels correlate with estradiol levels in male and female COVID-19 patients (R2=0.216, =0.0009). Male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment in the course of their ICU stay (p=0.0009). CONCLUSIONS We identified high estradiol and low testosterone levels as a hallmark of critically ill male COVID-19 patients. Elevated estradiol levels in critically ill male COVID-19 patients were positively associated with IFN-γ levels and increased risk for ECMO requirement.
- Published
- 2021
27. Investigation of activin A in inflammatory responses of the testis and its role in the development of testicular fibrosis
- Author
-
A. Christine Kauerhof, Mark P. Hedger, Adrian Pilatz, Hans-Christian Schuppe, Sabine Kliesch, Daniela Fietz, Kate A. Loveland, Sudhanshu Bhushan, Nour Nicolas, Eva Wahle, Nigel P. Groome, Martin Bergmann, Andreas Meinhardt, and Monika Fijak
- Subjects
Male ,Follistatin ,Orchitis ,PTPRC ,Andrology ,Mice ,03 medical and health sciences ,Hydroxyproline ,chemistry.chemical_compound ,0302 clinical medicine ,Fibrosis ,Testis ,Animals ,Humans ,Medicine ,Spermatogenesis ,Infertility, Male ,030304 developmental biology ,0303 health sciences ,030219 obstetrics & reproductive medicine ,biology ,business.industry ,Rehabilitation ,Obstetrics and Gynecology ,medicine.disease ,Activins ,Fibronectins ,Fibronectin ,Reproductive Medicine ,chemistry ,Testicular fibrosis ,biology.protein ,Tumor necrosis factor alpha ,Collagen ,business - Abstract
STUDY QUESTION Does activin A contribute to testicular fibrosis under inflammatory conditions? SUMMARY ANSWER Our results show that activin A and key fibrotic proteins are increased in human testicular biopsies with leukocytic infiltrates and impaired spermatogenesis and in murine experimental autoimmune orchitis (EAO) and that activin A stimulates fibrotic responses in peritubular cells (PTCs) and NIH 3T3 fibroblasts. WHAT IS KNOWN ALREADY Fibrosis is a feature of EAO. Activin A, a regulator of fibrosis, was increased in testes of mice with EAO and its expression correlated with severity of the disease. STUDY DESIGN, SIZE, DURATION This is a cross-sectional and longitudinal study of adult mice immunized with testicular homogenate (TH) in adjuvant to induce EAO, collected at 30 (n = 6), 50 (n = 6) and 80 (n = 5) days after first immunization. Age-matched mice injected with adjuvant alone (n = 14) and untreated mice (n = 15) were included as controls. TH-immunized mice with elevated endogenous follistatin, injected with a non-replicative recombinant adeno-associated viral vector carrying a gene cassette of follistatin (rAAV-FST315; n = 3) or vector with an empty cassette (empty vector controls; n = 2) 30 days prior to the first immunization, as well as appropriate adjuvant (n = 2) and untreated (n = 2) controls, were also examined. Human testicular biopsies showing focal inflammatory lesions associated with impaired spermatogenesis (n = 7) were included. Biopsies showing intact spermatogenesis without inflammation, from obstructive azoospermia patients, served as controls (n = 7). Mouse primary PTC and NIH 3T3 fibroblasts were stimulated with activin A and follistatin 288 (FST288) to investigate the effect of activin A on the expression of fibrotic markers. Production of activin A by mouse primary Sertoli cells (SCs) was also investigated. PARTICIPANTS/MATERIALS, SETTING, METHODS Testicular RNA and protein extracts collected from mice at days 30, 50 and 80 after first immunization were used for analysis of fibrotic marker genes and proteins, respectively. Total collagen was assessed by hydroxyproline assay and fibronectin; collagen I, III and IV, α-smooth muscle actin (α-SMA) expression and phosphorylation of suppressor of mothers against decapentaplegic (SMAD) family member 2 were measured by western blot. Immunofluorescence was used to detect fibronectin. Fibronectin (Fn), αSMA (Acta2), collagen I (Col1a2), III (Col3a1) and IV (Col4a1) mRNA in PTC and NIH 3T3 cells treated with activin A and/or FST288 were measured by quantitative RT-PCR (qRT-PCR). Activin A in SC following tumour necrosis factor (TNF) or FST288 stimulation was measured by ELISA. Human testicular biopsies were analysed by qRT-PCR for PTPRC (CD45) and activin A (INHBA), hydroxyproline assay and immunofluorescence. MAIN RESULTS AND THE ROLE OF CHANCE Production of activin A by SC was stimulated by 25 and 50 ng/ml TNF (P LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION A limited number of human testicular specimens was available for the study. Part of the study was performed in vitro, including NIH 3T3 cells as a surrogate for testicular fibroblasts. WIDER IMPLICATIONS OF THE FINDINGS Resident fibroblasts and PTC may contribute to the progression of testicular fibrosis following inflammation, and activin A is implicated as a key mediator of this process. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the National Health and Medical Research Council of Australia, the Victorian Government’s Operational Infrastructure Support Program and the International Research Training Group between Justus Liebig University (Giessen) and Monash University (Melbourne) (GRK 1871/1–2) on `Molecular pathogenesis on male reproductive disorders’ funded by the Deutsche Forschungsgemeinschaft and Monash University. The authors declare no competing financial interests.
- Published
- 2019
28. Dexamethasone improves therapeutic outcomes in a preclinical bacterial epididymitis mouse model
- Author
-
Carsten Rudat, Kate L Loveland, Sudhanshu Bhushan, Rukmali Wijayarathna, Mark P. Hedger, Adrian Pilatz, Ralf Middendorff, Swapnila Pant, Julia Kautz, Britta Klein, Andreas Kispert, and Andreas Meinhardt
- Subjects
Male ,Epithelial-Mesenchymal Transition ,Anti-Inflammatory Agents ,Drug Evaluation, Preclinical ,Physiology ,Levofloxacin ,Adaptive Immunity ,Dexamethasone ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Animals ,Humans ,Medicine ,Infertility, Male ,030304 developmental biology ,Subclinical infection ,Epididymis ,Epididymitis ,0303 health sciences ,030219 obstetrics & reproductive medicine ,biology ,business.industry ,Rehabilitation ,Obstetrics and Gynecology ,medicine.disease ,Fibrosis ,Bacterial Load ,Anti-Bacterial Agents ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Immunoglobulin M ,Reproductive Medicine ,Immunoglobulin G ,biology.protein ,Cytokines ,Drug Therapy, Combination ,business ,medicine.drug - Abstract
STUDY QUESTION Can dexamethasone improve infertility-related cauda epididymidal tissue damage caused by bacterial epididymitis? SUMMARY ANSWER Dexamethasone in addition to anti-microbial treatment effectively reduces long-term deleterious epididymal tissue damage by dampening the host’s adaptive immune response. WHAT IS KNOWN ALREADY Despite effective anti-microbial treatment, ~40% of patients with epididymitis experience subsequent sub- or infertility. An epididymitis mouse model has shown that the host immune response is mainly responsible for the magnitude of epididymal tissue damage that is fundamentally causative of the subsequent fertility issues. STUDY DESIGN, SIZE, DURATION Bacterial epididymitis was induced in male mice by using uropathogenic Escherichia coli (UPEC). From Day 3 after infection onwards, mice were treated with daily doses of levofloxacin (20 mg/kg, total n = 12 mice), dexamethasone (0.5 mg/kg, total n = 9) or both in combination (total n = 11) for seven consecutive days. Control animals were left untreated, i.e. given no interventional treatment following UPEC infection (total n = 11). Half of the animals from each group were killed either at 10 or 31 days post-infection. PARTICIPANTS/MATERIALS, SETTING, METHODS A mouse model of induced bacterial epididymitis was applied to adult male C57BL/6J mice. At the respective endpoints (10 or 31 days post-infection), epididymides were collected. Effectiveness of antibiotic treatment was assessed by plating of epididymal homogenates onto lysogeny broth agar plates. Overall tissue morphology and the degree and nature of tissue damage were assessed histologically. Quantitative RT-PCR was used to assess local cytokine transcript levels. Blood was drawn and serum analysed for systemic IgG and IgM levels by ELISA. In addition, correlation analyses of clinical data and serum-analyses of IgG and IgM levels in patients with epididymitis were performed. MAIN RESULTS AND THE ROLE OF CHANCE The addition of dexamethasone to the standard anti-microbial treatment did not further worsen epididymal tissue integrity. In fact, an obviously dampened immune response and reduced tissue reaction/damage was observed at both 10 and 31 days post-infection following combined treatment. More specifically, epididymal duct continuity was preserved, enabling sperm transit. In contrast, in untreated or antibiotic-treated animals, damage of the epididymal duct and duct constrictions were observed, associated with a lack of cauda spermatozoa. In line with the bacteriostatic/bactericidal effect of levofloxacin (alone as well as in combination), local cytokine transcript levels were significantly and similarly reduced in animals treated with levofloxacin alone (P LIMITATIONS, REASONS FOR CAUTION Breeding studies to address the fertility-protecting effect of the combined treatment were not possible in the experimental animals because the vas deferens was ligated (model specific). WIDER IMPLICATIONS OF THE FINDINGS Whereas innate immunity is necessary and involved in acute bacterial clearance, adaptive immunity seems to be responsible for long-term, subclinical immunological activities that may negatively affect the pathogenesis of bacterial epididymitis even after effective bacterial eradication. These effects can be reduced in mice by the additional treatment with dexamethasone. This immunological characteristic of bacterial epididymitis shows similarities to the Jarisch–Herxheimer reaction known from other types of bacterial infection. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by grants from the Deutsche Forschungsgemeinschaft, Monash University and the Medical Faculty of Justus-Liebig University to the International Research Training Group on ‘Molecular pathogenesis of male reproductive disorders’ (GRK 1871). R.W., K.L.L. and M.P.H. were supported by grants from the National Health and Medical Research Council of Australia (ID1079646, ID1081987, ID1020269 and ID1063843) and by the Victorian Government’s Operational Infrastructure Support Program. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER No clinical trial involved.
- Published
- 2019
29. Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion
- Author
-
Jun Lv, Zhi H. Zheng, Zi J Zhou, Hui Yang, Qiu Y. Huang, Xiao H. Wang, Andreas Meinhardt, Jörg Klug, Hui-Yao Lan, Patrick Ming-Kuen Tang, Gunter Fingerle-Rowson, Ying Tang, Jin H Li, Xiao R. Huang, Zhi J. He, and An P. Xu
- Subjects
Male ,0301 basic medicine ,CD74 ,medicine.medical_treatment ,Kidney ,urologic and male genital diseases ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Chemokine CCL2 ,Mice, Knockout ,NF-kappa B ,Acute kidney injury ,Acute Kidney Injury ,Middle Aged ,female genital diseases and pregnancy complications ,Intramolecular Oxidoreductases ,Cytokine ,medicine.anatomical_structure ,Creatinine ,Reperfusion Injury ,030220 oncology & carcinogenesis ,Disease Progression ,Molecular Medicine ,Original Article ,Female ,renal inflammation ,Adult ,medicine.medical_specialty ,Urinary system ,chemical and pharmacologic phenomena ,macrophage migration inhibitory factor (MIF) ,03 medical and health sciences ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Animals ,Humans ,Macrophage Migration-Inhibitory Factors ,CXCL15 ,Aged ,urogenital system ,business.industry ,Histocompatibility Antigens Class II ,Original Articles ,Cell Biology ,medicine.disease ,cytokines ,Antigens, Differentiation, B-Lymphocyte ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Macrophage migration inhibitory factor ,business - Abstract
Macrophage migration inhibitory factor (MIF) is pleiotropic cytokine that has multiple effects in many inflammatory and immune diseases. This study reveals a potential role of MIF in acute kidney injury (AKI) in patients and in kidney ischemic reperfusion injury (IRI) mouse model in MIF wild‐type (WT) and MIF knockout (KO) mice. Clinically, plasma and urinary MIF levels were largely elevated at the onset of AKI, declined to normal levels when AKI was resolved and correlated tightly with serum creatinine independent of disease causes. Experimentally, MIF levels in plasma and urine were rapidly elevated after IRI‐AKI and associated with the elevation of serum creatinine and the severity of tubular necrosis, which were suppressed in MIF KO mice. It was possible that MIF may mediate AKI via CD74/TLR4‐NF‐κB signalling as mice lacking MIF were protected from AKI by largely suppressing CD74/TLR‐4‐NF‐κB associated renal inflammation, including the expression of MCP‐1, TNF‐α, IL‐1β, IL‐6, iNOS, CXCL15(IL‐8 in human) and infiltration of macrophages, neutrophil, and T cells. In conclusion, our study suggests that MIF may be pathogenic in AKI and levels of plasma and urinary MIF may correlate with the progression and regression of AKI.
- Published
- 2019
30. Immunologisch bedingte Infertilität
- Author
-
Andreas Meinhardt, Hans-Christian Schuppe, and Hermann M. Behre
- Published
- 2021
31. Two populations of self-maintaining monocyte-independent macrophages exist in adult epididymis and testis
- Author
-
Kathrin Klee, Andreas Meinhardt, Monika Fijak, Christian Schulz, Melanie Greter, Burkhard Becher, Thomas Ulas, Slava Epelman, Sudhanshu Bhushan, Yiming Wang, Christiane Pleuger, Dilay Cansever, Gabriel Livera, Joachim L. Schultze, Qingzhi Liu, Svetoslav Chakarov, Britta Klein, Yalong Yang, Andreas Schlitzer, Florent Ginhoux, Christopher Stremmel, Zhaoyuan Liu, Zhe-Xiong Lian, Crystal Kantores, Sébastien Messiaen, Kristian Händler, Ming Wang, Wentao Ma, Delphine Moison, and Tobias Weinberger
- Subjects
0301 basic medicine ,Male ,Biology ,testis ,immunology [Infertility, Male] ,Monocytes ,metabolism [Epididymis] ,03 medical and health sciences ,immunology [Monocytes] ,Mice ,0302 clinical medicine ,Immune system ,Testis ,medicine ,physiopathology [Infertility, Male] ,Macrophage ,Animals ,Cell Lineage ,Progenitor cell ,Yolk sac ,Infertility, Male ,macrophgaes ,Epididymis ,Multidisciplinary ,metabolism [Infertility, Male] ,immunology [Testis] ,Monocyte ,Macrophages ,Cell Differentiation ,immunology [Macrophages] ,Biological Sciences ,Cell biology ,Mice, Inbred C57BL ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,ontogeny ,metabolism [Macrophages] ,Bone marrow ,ddc:500 ,metabolism [Testis] ,immunology [Epididymis] ,monocytes ,epididymis ,030215 immunology - Abstract
Macrophages are the principal immune cells of the epididymis and testis, but their origins, heterogeneity, development, and maintenance are not well understood. Here, we describe distinct populations of epididymal and testicular macrophages that display an organ-specific cellular identity. Combining in vivo fate-mapping, chimeric and parabiotic mouse models with in-depth cellular analyses, we found that CD64(hi)MHCII(lo) and CD64(lo)MHCII(hi) macrophage populations of epididymis and testis arise sequentially from yolk sac erythro-myeloid progenitors, embryonic hematopoiesis, and nascent neonatal monocytes. While monocytes were the major developmental source of both epididymal and testicular macrophages, both populations self-maintain in the steady-state independent of bone marrow hematopoietic precursors. However, after radiation-induced macrophage ablation or during infection, bone marrow-derived circulating monocytes are recruited to the epididymis and testis, giving rise to inflammatory macrophages that promote tissue damage. These results define the layered ontogeny, maintenance and inflammatory response of macrophage populations in the male reproductive organs.
- Published
- 2020
32. Targeted disruption of galectin 3 in mice delays the first wave of spermatogenesis and increases germ cell apoptosis
- Author
-
Tao, Lei, Sandra M, Blois, Nancy, Freitag, Martin, Bergmann, Sudhanshu, Bhushan, Eva, Wahle, Annie Chi-Chun, Huang, Hung-Lin, Chen, Michaela F, Hartmann, Stefan A, Wudy, Fu-Tong, Liu, Andreas, Meinhardt, and Monika, Fijak
- Subjects
Male ,Mice, Inbred C57BL ,Mice, Knockout ,Mice ,Sertoli Cells ,Galectin 3 ,Animals ,Leydig Cells ,Apoptosis ,Testosterone ,Follicle Stimulating Hormone ,Spermatogenesis ,Spermatozoa - Abstract
Galectin 3 is a multifunctional lectin implicated in cellular proliferation, differentiation, adhesion, and apoptosis. This lectin is broadly expressed in testicular somatic cells and germ cells, and is upregulated during testicular development. Since the role of galectin 3 in testicular function remains elusive, we aimed to characterize the role of galectin 3 in testicular physiology. We found that galectin 3 transgenic mice (Lgals3
- Published
- 2020
33. Uropathogenic Escherichia coli Virulence Factor α-Hemolysin Reduces Histone Acetylation to Inhibit Expression of Proinflammatory Cytokine Genes
- Author
-
Ming Wang, Marek Bartkuhn, Yiming Zhang, Trinad Chakraborty, Sudhanshu Bhushan, Zhengguo Zhang, Sandra B. Hake, Yu Zhang, Zhankui Jia, Hamid Hossain, Andreas Meinhardt, and Melanie Markmann
- Subjects
0301 basic medicine ,Virulence Factors ,medicine.medical_treatment ,Biology ,urologic and male genital diseases ,medicine.disease_cause ,Virulence factor ,Chromatin remodeling ,Microbiology ,Proinflammatory cytokine ,Histones ,03 medical and health sciences ,Hemolysin Proteins ,Mice ,0302 clinical medicine ,Immune system ,medicine ,Immunology and Allergy ,Animals ,Humans ,Uropathogenic Escherichia coli ,Escherichia coli ,Escherichia coli Infections ,Innate immune system ,Escherichia coli Proteins ,Acetylation ,female genital diseases and pregnancy complications ,Immunity, Innate ,030104 developmental biology ,Infectious Diseases ,Cytokine ,Histone ,030220 oncology & carcinogenesis ,Host-Pathogen Interactions ,Urinary Tract Infections ,biology.protein ,Cytokines - Abstract
Urinary tract infections are common and costly diseases affecting millions of people. Uropathogenic Escherichia coli (UPEC) is a primary cause of these infections and has developed multiple strategies to avoid the host immune response. Here, we dissected the molecular mechanisms underpinning UPEC inhibition of inflammatory cytokine in vitro and in vivo. We found that UPEC infection simulates nuclear factor-κB activation but does not result in transcription of cytokine genes. Instead, UPEC-mediated suppression of the metabolic enzyme ATP citrate lyase results in decreased acetyl-CoA levels, leading to reduced H3K9 histone acetylation in the promotor region of CXCL8. These effects were dependent on the UPEC virulence factor α-hemolysin and were reversed by exogenous acetate. In a murine cystitis model, prior acetate supplementation rapidly resolved UPEC-elicited immune responses and improved tissue recovery. Thus, upon infection, UPEC rearranges host cell metabolism to induce chromatin remodeling processes that subvert expression of host innate immune response genes.
- Published
- 2020
34. Sex hormone and metabolic dysregulations are associated with critical illness in male Covid-19 patients
- Author
-
Lothar Kreienbrock, Henning Jacobsen, Karin Klingel, Stephanie Stanelle-Bertram, Jens Aberle, Fabian Stoll, Zacharias Mueller, Dominik Jarczak, Andreas Meinhardt, Andreas Kloetgen, Thomas Renné, Bettina Schneider, Ann Parplys, Maria Schroeder, Axel Nierhaus, Stefan Kluge, Jens Hiller, berfin schaumburg, Guelsah Gabriel, Manuela Peschka, Tian Bai, Hartmut Schlueter, Joerg Heeren, Alice C. McHardy, Martin Zickler, Geraldine de Heer, and Sven Peine
- Subjects
medicine.medical_specialty ,business.industry ,Retrospective cohort study ,medicine.disease ,Intensive care unit ,Obesity ,law.invention ,law ,Dihydrotestosterone ,Internal medicine ,Intensive care ,Medicine ,SOFA score ,business ,Testosterone ,Hormone ,medicine.drug - Abstract
Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide and pose a major public health burden. There is increasing evidence that men are more likely to die from SARS-CoV-2 infection than women. However, underlying factors that mediate the observed sex bias in coronavirus disease 2019 (COVID-19) remain unknown. Methods. In this retrospective cohort, we included COVID-19 patients who were admitted to an Intensive Care Unit at the University Hospital Hamburg-Eppendorf, Germany. We obtained demographic data of all patients who were discharged or had died by 29th April 2020. We systematically analyzed sex hormones as well as cytokine and chemokine responses in male and female patients with laboratory-confirmed SARS-CoV-2 infections upon hospital admission. We used uni- and multivariable linear regression methods to identify potential risk factors for disease severity in males and females. Findings. All enrolled patients (n=45; n=35 males and n=10 females) presented comorbidities with hypertension being the most common (45.7% in males; 40% in females), followed by cancer (35% in males; 40% in females), obesity (34.3% in males and 30% in females), type II diabetes (25.7% in males and 20% in females) and chronic heart diseases (8.6% in males and 0% in females). We detected that the vast majority of male COVID-19 patients present low testosterone (68.6%) and low dihydrotestosterone (48.6%) levels. In contrast, most female COVID-19 patients have elevated testosterone levels (60%) without alterations in dihydrotestosterone levels. Both, female and male COVID-19 patients may present elevated estradiol levels (45.7% in males and 40% in females). Disease severity defined by SOFA score correlates with elevated cytokine responses (e.g. IL-6) in males and IL-2 in females. In male COVID-19 patients, testosterone levels negatively correlate with inflammatory IL-2 and IFN-γ, whereas estradiol levels positively correlate with the inflammatory cytokine IL-6. Vice versa, in female COVID-19 patients, testosterone levels positively correlate with inflammatory cytokines (e.g. IL-6). Interpretation. We here show that critically ill male COVID-19 patients suffer from severe testosterone and dihydrotestosterone deficiencies. Both androgens are required to mount antiviral immune responses to combat infection in males.
- Published
- 2020
35. Microenvironmental signals govern the cellular identity of testicular macrophages
- Author
-
Ming Wang, Christian Schulz, Sudhanshu Bhushan, and Andreas Meinhardt
- Subjects
Male ,0301 basic medicine ,Immunology ,Population ,Cell ,Orchitis ,Stimulation ,Biology ,Immunophenotyping ,Proinflammatory cytokine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immune privilege ,Antigens, CD ,Testis ,medicine ,Animals ,Humans ,Immunology and Allergy ,Testosterone ,Spermatogenesis ,education ,Blood-Testis Barrier ,education.field_of_study ,Macrophages ,Cell Biology ,Spermatozoa ,Phenotype ,Immunity, Innate ,Cell biology ,Self Tolerance ,030104 developmental biology ,medicine.anatomical_structure ,Cellular Microenvironment ,Immune System ,M2 phenotype ,Prostaglandins ,Cytokines ,Corticosterone ,030215 immunology - Abstract
Testicular macrophages (TM) comprise the largest immune cell population in the mammalian testis. They are characterized by a subdued proinflammatory response upon adequate stimulation, and a polarization toward the immunoregulatory and immunotolerant M2 phenotype. This enables them to play a relevant role in supporting the archetypical functions of the testis, namely spermatogenesis and steroidogenesis. During infection, the characteristic blunted immune response of TM reflects the need for a delicate balance between a sufficiently strong reaction to counteract invading pathogens, and the prevention of excessive proinflammatory cytokine levels with the potential to disturb or destroy spermatogenesis. Local microenvironmental factors that determine the special phenotype of TM have just begun to be unraveled, and are discussed in this review. The immunosuppressive M2 macrophage phenotype of testicular macrophages is determined by the testicular microenvironment to maintain the immune privilege of the testis.
- Published
- 2018
36. Region-specific immune responses to autoimmune epididymitis in the murine reproductive tract
- Author
-
Mark P. Hedger, Rukmali Wijayarathna, Nour Nicolas, Alen Pasalic, Sneha Biniwale, Rosemary Genovese, Andreas Meinhardt, Monika Fijak, Julie A Muir, Rama Ravinthiran, and Kate L Loveland
- Subjects
0301 basic medicine ,Male ,endocrine system ,Histology ,Gene Expression ,Inflammation ,medicine.disease_cause ,Pathology and Forensic Medicine ,Autoimmunity ,Autoimmune Diseases ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immune system ,Fibrosis ,Medicine ,Animals ,Epididymis ,Epididymitis ,urogenital system ,business.industry ,Cell Biology ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Orchitis ,Tumor necrosis factor alpha ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Epididymitis is a common pathology of the male reproductive tract, potentially leading to infertility. Studies on bacterial epididymitis indicate that the cauda epididymis is more susceptible to inflammatory damage than the caput. These regional differences in immunoregulation are further investigated using an experimental autoimmune epididymo-orchitis model. Adult mice were immunized against testicular antigens and tissues were collected at 30 and 50 days following the first immunization. Epididymitis developed progressively; 70% of the mice developed disease at 30 days after the initial immunization and 93% at 50 days. Epididymitis was characterized by epithelial damage, immune cell infiltrates and fibrosis in the cauda, with minimal changes in the corpus, while the caput was unaffected. The incidence of epididymitis was greater than that of orchitis but similar to vasitis. The severity of epididymitis was positively correlated with the orchitis severity. Expression of key genes implicated in epididymal immunoregulation, inflammation and fibrosis, such as Ido1, Tnf, Tgfb1, Ccl2, Il1b, Il10, Cx3cl1 and Col1a1, was unchanged in the caput but increased in proportion to damage severity in the cauda at 50 days. Activin receptor mRNA expression in the cauda was negatively correlated with disease severity. These data suggest that the cauda is highly susceptible to inflammatory damage following an autoimmune challenge but the caput is minimally affected. This may be because the cauda is required to combat ascending infections through a robust inflammatory response, while the caput provides a more tolerogenic environment in order to protect the auto-antigenic sperm released from the testis.
- Published
- 2019
37. Activin over-expression in the testis of mice lacking the inhibin α-subunit gene is associated with androgen deficiency and regression of the male reproductive tract
- Author
-
David M. de Kretser, Rukmali Wijayarathna, Kate A. Loveland, Helen Ludlow, Andreas Meinhardt, Ralf Middendorff, Nigel P. Groome, and Mark P. Hedger
- Subjects
Male ,0301 basic medicine ,Aging ,Follistatin ,endocrine system ,medicine.medical_specialty ,Somatic cell ,Biochemistry ,03 medical and health sciences ,Vas Deferens ,0302 clinical medicine ,Endocrinology ,Testicular Neoplasms ,Stroma ,Internal medicine ,Testis ,Androgen deficiency ,Gene expression ,medicine ,Animals ,Inhibins ,Molecular Biology ,Epididymis ,030219 obstetrics & reproductive medicine ,biology ,Leydig cell ,Vas deferens ,medicine.disease ,Activins ,Mice, Inbred C57BL ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,embryonic structures ,Androgens ,biology.protein ,Stromal Cells ,hormones, hormone substitutes, and hormone antagonists - Abstract
Regionalised interaction of the activins, follistatin and inhibin was investigated in the male reproductive tract of mice lacking the inhibin α-subunit (Inha-/-). Serum and intratesticular activin B, although not activin A and follistatin, were increased in Inha-/- mice at 25 days of age, but all three proteins were elevated at 56 days. None of these proteins were altered within the epididymis and vas deferens at either age. At 25 days, histology of the epididymis and vas deferens was similar to wild-type. At 56 days, the testis contained extensive somatic cell tumours, leading to Leydig cell regression and testosterone deficiency. The epididymis and vas deferens showed epithelial regression and increased prominence of the interstitial stroma. Immunoregulatory and fibrotic gene expression in the epididymis and vas deferens were unchanged. Thus, absence of the inhibin α-subunit has marginal effects on activins in the epididymis and vas deferens, and regression of these tissues is associated with androgen deficiency.
- Published
- 2018
38. Infectious, inflammatory and ‘autoimmune’ male factor infertility: how do rodent models inform clinical practice?
- Author
-
Sudhanshu Bhushan, Andreas Meinhardt, Monika Fijak, Kenneth S. K. Tung, Nour Nicolas, Adrian Pilatz, Mark P. Hedger, Vera Michel, and Hans-Christian Schuppe
- Subjects
Male ,0301 basic medicine ,Infertility ,Orchitis ,Rodentia ,Review ,Disease ,Infections ,Autoimmune Diseases ,Male infertility ,03 medical and health sciences ,Obstetrics and Gynaecology ,medicine ,Animals ,Humans ,Infertility, Male ,Inflammation ,Autoimmune disease ,business.industry ,Vasectomy ,Obstetrics and Gynecology ,medicine.disease ,Testicular sperm extraction ,3. Good health ,Disease Models, Animal ,030104 developmental biology ,Reproductive Medicine ,Immunology ,Epididymitis ,business - Abstract
Background Infection and inflammation of the reproductive tract are significant causes of male factor infertility. Ascending infections caused by sexually transmitted bacteria or urinary tract pathogens represent the most frequent aetiology of epididymo-orchitis, but viral, haematogenous dissemination is also a contributory factor. Limitations in adequate diagnosis and therapy reflect an obvious need for further understanding of human epididymal and testicular immunopathologies and their contribution to infertility. A major obstacle for advancing our knowledge is the limited access to suitable tissue samples. Similarly, the key events in the inflammatory or autoimmune pathologies affecting human male fertility are poorly amenable to close examination. Moreover, the disease processes generally have occurred long before the patient attends the clinic for fertility assessment. In this regard, data obtained from experimental animal models and respective comparative analyses have shown promise to overcome these restrictions in humans. Objective and rationale This narrative review will focus on male fertility disturbances caused by infection and inflammation, and the usefulness of the most frequently applied animal models to study these conditions. Search methods An extensive search in Medline database was performed without restrictions until January 2018 using the following search terms: 'infection' and/or 'inflammation' and 'testis' and/or 'epididymis', 'infection' and/or 'inflammation' and 'male genital tract', 'male infertility', 'orchitis', 'epididymitis', 'experimental autoimmune' and 'orchitis' or 'epididymitis' or 'epididymo-orchitis', antisperm antibodies', 'vasectomy'. In addition to that, reference lists of primary and review articles were reviewed for additional publications independently by each author. Selected articles were verified by each two separate authors and discrepancies discussed within the team. Outcomes There is clear evidence that models mimicking testicular and/or epididymal inflammation and infection have been instructive in a better understanding of the mechanisms of disease initiation and progression. In this regard, rodent models of acute bacterial epididymitis best reflect the clinical situation in terms of mimicking the infection pathway, pathogens selected and the damage, such as fibrotic transformation, observed. Similarly, animal models of acute testicular and epididymal inflammation using lipopolysaccharides show impairment of reproduction, endocrine function and histological tissue architecture, also seen in men. Autoimmune responses can be studied in models of experimental autoimmune orchitis (EAO) and vasectomy. In particular, the early stages of EAO development showing inflammatory responses in the form of peritubular lymphocytic infiltrates, thickening of the lamina propria of affected tubules, production of autoantibodies against testicular antigens or secretion of pro-inflammatory mediators, replicate observations in testicular sperm extraction samples of patients with 'mixed atrophy' of spermatogenesis. Vasectomy, in the form of sperm antibodies and chronic inflammation, can also be studied in animal models, providing valuable insights into the human response. Wider implications This is the first comprehensive review of rodent models of both infectious and autoimmune disease of testis/epididymis, and their clinical implications, i.e. their importance in understanding male infertility related to infectious and non-infectious/autoimmune disease of the reproductive organs.
- Published
- 2018
39. Induction of experimental autoimmune orchitis in mice: responses to elevated circulating levels of the activin-binding protein, follistatin
- Author
-
Peter G. Stanton, Kate L Loveland, Mark P. Hedger, Nour Nicolas, Justin L. Chen, D. M. De Kretser, Sudhanshu Bhushan, Paul Gregorevic, Susan Hayward, Andreas Meinhardt, Monika Fijak, and Julie A Muir
- Subjects
Male ,0301 basic medicine ,Follistatin ,endocrine system ,Embryology ,medicine.medical_specialty ,medicine.medical_treatment ,Apoptosis ,Orchitis ,Inflammation ,Myostatin ,Autoimmune Diseases ,03 medical and health sciences ,Endocrinology ,Fibrosis ,Internal medicine ,Testis ,medicine ,Animals ,Blood-Testis Barrier ,Blood–testis barrier ,biology ,business.industry ,Gene Transfer Techniques ,Obstetrics and Gynecology ,Cell Biology ,medicine.disease ,Recombinant Proteins ,Activins ,Up-Regulation ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,Gene Expression Regulation ,Reproductive Medicine ,embryonic structures ,Disease Progression ,biology.protein ,Inflammation Mediators ,medicine.symptom ,business ,Biomarkers ,hormones, hormone substitutes, and hormone antagonists - Abstract
Experimental autoimmune orchitis (EAO) is a rodent model of chronic testicular inflammation that mimics the pathology observed in some types of human infertility. In a previous study, testicular expression of the inflammatory/immunoregulatory cytokine, activin A, was elevated in adult mice during the onset of EAO, indicating a potential role in the regulation of the disease. Consequently, we examined the development of EAO in mice with elevated levels of follistatin, an endogenous activin antagonist, as a potential therapeutic approach to testicular inflammation. Prior to EAO induction, mice received a single intramuscular injection of a non-replicative recombinant adeno-associated viral vector carrying a gene cassette of the circulating form of follistatin, FST315 (FST group). Serum follistatin levels were increased 5-fold in the FST group compared with the control empty vector (EV) group at 30 and 50 days of EAO, but intra-testicular levels of follistatin or activin A were not significantly altered. Induction of EAO was reduced, but not prevented, with mild-to-severe damage in 75% of the EV group and 40% of the FST group, at 50 days following immunisation with testicular homogenate. However, the EAO damage score (based on disruption of the blood–testis barrier, apoptosis, testicular damage and fibrosis) and extent of intratesticular inflammation (expression of inflammatory mediators) were directly proportional to the levels of activin A measured in the testis at 50 days. These data implicate activin A in the progression of EAO, thereby providing a potential therapeutic target; however, elevating circulating follistatin levels were not sufficient to prevent EAO development.
- Published
- 2017
40. Characterization of the Micro-Environment of the Testis that Shapes the Phenotype and Function of Testicular Macrophages
- Author
-
Günter Lochnit, Andreas Meinhardt, Monika Fijak, Huanpeng Gu, Hamid Hossain, Sudhanshu Bhushan, Rolf M. Nüsing, Lutz Konrad, Ming Wang, Trinad Chakraborty, Melanie Markmann, Lizong Zhang, Stefan A. Wudy, and Michaela F. Hartmann
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Immunology ,Population ,Antigens, Differentiation, Myelomonocytic ,Receptors, Cell Surface ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Glucocorticoid receptor ,Immune privilege ,Antigens, CD ,Internal medicine ,Testis ,medicine ,Animals ,Immunology and Allergy ,education ,Receptor ,Cells, Cultured ,education.field_of_study ,030219 obstetrics & reproductive medicine ,Innate immune system ,Tumor Necrosis Factor-alpha ,Macrophages ,Granulocyte-Macrophage Colony-Stimulating Factor ,Extracellular Fluid ,M2 Macrophage ,Phenotype ,Immunity, Innate ,Interleukin-10 ,Rats ,Cell biology ,030104 developmental biology ,Endocrinology ,Cellular Microenvironment ,Corticosterone ,CD163 - Abstract
Macrophages are important in the activation of innate immune responses and in a tissue-specific manner in the maintenance of organ homeostasis. Testicular macrophages (TM), which reside in the testicular interstitial space, comprise the largest leukocyte population in the testes and are assumed to play a relevant function in maintaining testicular immune privilege. Numerous studies have indicated that the interstitial fluid (IF) surrounding the TM has immunosuppressive properties, which may influence the phenotype of TM. However, the identity of the immunosuppressive molecules present in the IF is poorly characterized. We show that the rat testicular IF shifted GM-CSF–induced M1 toward the M2 macrophage phenotype. IF-polarized M2 macrophages mimic the properties of TM, such as increased expression of CD163, high secretion of IL-10, and low secretion of TNF-α. In addition, IF-polarized macrophages display immunoregulatory functions by inducing expansion of immunosuppressive regulatory T cells. We further found that corticosterone was the principal immunosuppressive molecule present in the IF and that the glucocorticoid receptor is needed for induction of the testis-specific phenotype of TM. In addition, TM locally produce small amounts of corticosterone, which suppresses the basal expression of inflammatory genes as a means to render TM refractory to inflammatory stimuli. Taken together, these results suggest that the corticosterone present in the testicular environment shapes the immunosuppressive function and phenotype of TM and that this steroid may play an important role in the establishment and sustenance of the immune privilege of the testis.
- Published
- 2017
41. Differential tissue-specific damage caused by bacterial epididymo-orchitis in the mouse
- Author
-
Britta Klein, Kate L Loveland, Stefan Günther, Ralf Middendorff, Andreas Meinhardt, Sudhanshu Bhushan, and Mark P. Hedger
- Subjects
Male ,Embryology ,endocrine system ,beta-Defensins ,Antimicrobial peptides ,Orchitis ,Biology ,testis ,GPI-Linked Proteins ,Andrology ,Transcriptome ,Mice ,In vivo ,Immunity ,Genetics ,medicine ,Animals ,Uropathogenic Escherichia coli ,Molecular Biology ,Escherichia coli Infections ,Original Research ,Epididymis ,Epididymitis ,urogenital system ,Gene Expression Profiling ,Obstetrics and Gynecology ,LYPD8 ,Cell Biology ,uropathogenic E. coli ,beta-defensin ,medicine.disease ,spermatogenesis ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Beta defensin ,Reproductive Medicine ,Urinary Tract Infections ,Spermatogenesis ,epididymo-orchitis ,Developmental Biology - Abstract
Ascending bacterial urinary tract infections can cause epididymo-orchitis. In the cauda epididymidis, this frequently leads to persistent tissue damage. Less coherent data is available concerning the functional consequences of epididymo-orchitis on testis and caput epididymidis. This in vivo study addresses the functional and spatial differences in responsiveness of murine epididymis and testis to infection with uropathogenic Escherichia coli (UPEC). Whole transcriptome analysis (WTA) was performed on testis, caput, corpus and cauda epididymidis of adult C57BL/6 J wildtype mice. Following UPEC-induced epididymo-orchitis in these mice, epididymal and testicular tissue damage was evaluated histologically and semi-quantitatively at 10 days and 31 days post-inoculation. Expression of inflammatory markers and candidate antimicrobial genes were analysed by RT-qPCR. WTA revealed distinct differences in gene signatures between caput and cauda epididymidis, particularly amonst immunity-related genes. Cellular and molecular signs of testicular inflammation and disruption of spermatogenesis were noticed at day 10, but recovery was observed by day 31. In contrast to the cauda, the caput epididymidis did not reveal any signs of gross morphological damage or presence of pro-inflammatory processes despite confirmed infection. In contrast to beta-defensins, known UPEC-associated antimicrobial peptides (AMP), like Lcn2, Camp and Lypd8, were inherently highly expressed or upregulated in the caput following infection, potentially allowing an early luminal protection from UPEC. At the time points investigated, the caput epididymidis was protected from any obvious infection/inflammation-derived tissue damage. Studies addressing earlier time-points will conclude whether in the caput epididymidis a pro-inflammatory response is indeed not essential for effective protection from UPEC.
- Published
- 2019
42. UropathogenicEscherichia colicauses fibrotic remodelling of the epididymis
- Author
-
Julia M Young, Elke Stoschek, Andreas Meinhardt, Sudhanshu Bhushan, Ralf Middendorff, Kate L Loveland, Yonggang Duan, Mark P. Hedger, Vera Michel, and D. M. De Kretser
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,030219 obstetrics & reproductive medicine ,biology ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Antibiotics ,medicine.disease ,Epididymis ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Cytokine ,medicine.anatomical_structure ,Fibrosis ,In vivo ,medicine ,biology.protein ,Tumor necrosis factor alpha ,Epididymitis ,business ,Follistatin - Abstract
Despite antibiotic treatment, up to 40% of patients have impaired fertility after epididymitis due to serovars of Escherichia coli, a frequent pathogen. The reasons for infertility are unclear, but it may result from epididymal duct obstruction. To determine whether E. coli infection of the epididymis causes obstruction due to fibrosis, and to identify the key mediators, tissues from patients with epididymitis were assessed. Additionally, epididymitis was induced with uropathogenic E. coli (UPEC) or commensal serovars in wild-type and MyD88(-/-) mice, which are relatively unresponsive to bacterial pathogens. Epididymal organ cultures were treated with activin A and bacteria and their histology and levels of cytokines and fibrosis markers were analysed. Patients with epididymitis showed severe fibrosis of the epididymal duct. In mice, UPEC infection also caused fibrosis and ductal obstruction in the cauda epididymis. Levels of mRNA for fibrotic markers (α-smooth muscle actin, fibronectin) and cytokines (activin A, TNFα, IL-1α, IL-1β, IL-6) and total collagen levels were significantly elevated. This fibrotic response was blunted by the loss of MyD88. Activin A induced fibrosis in cultured epididymis, which was inhibited by the activin-binding protein follistatin. In summary, bacterial epididymitis causes fibrosis and obstruction. The milder tissue damage in Myd88(-/-) UPEC epididymitis highlights the importance of the host response to infection in causing epididymal damage. Elevated levels of activin A in vivo and fibrotic remodelling elicited by activin A in vitro indicate that this cytokine is a potential target for supplementary treatment to antibiotic therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
- Published
- 2016
43. Desialylation of Spermatozoa and Epithelial Cell Glycocalyx Is a Consequence of Bacterial Infection of the Epididymis
- Author
-
Christina E. Galuska, Vera Michel, Hans-Christian Schuppe, Philipp Christian, Sebastian P. Galuska, Andreas Meinhardt, Adrian Pilatz, Sudhanshu Bhushan, and Farhad Khosravi
- Subjects
Male ,0301 basic medicine ,Proteases ,Acrosome reaction ,Neuraminidase ,Biology ,Glycocalyx ,Sialidase ,Biochemistry ,Microbiology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Humans ,Uropathogenic Escherichia coli ,sialidase ,spermatozoa ,sialic acid ,glycosylation ,sperm ,glycosylation inhibitor ,bacterial pagthogenesis ,reproduction ,Acrosome ,Molecular Biology ,Epididymitis ,030219 obstetrics & reproductive medicine ,urogenital system ,Cell Biology ,Epididymis ,medicine.disease ,Spermatozoa ,N-Acetylneuraminic Acid ,Sialic acid ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Urinary Tract Infections ,Immunology ,Developmental Biology - Abstract
Urinary tract infections caused by uropathogenic Escherichia coli (UPEC) pathovars belong to the most frequent infections in humans. In men, pathogens can also spread to the genital tract via the continuous ductal system, eliciting bacterial prostatitis and/or epididymo-orchitis. Antibiotic treatment usually clears pathogens in acute epididymitis; however, the fertility of patients can be permanently impaired. Because a premature acrosome reaction was observed in an UPEC epididymitis mouse model, and sialidases on the sperm surface are considered to be activated via proteases of the acrosome, we aimed to investigate whether alterations of the sialome of epididymal spermatozoa and surrounding epithelial cells occur during UPEC infection. In UPEC-elicited acute epididymitis in mice, a substantial loss of N-acetylneuraminic acid residues was detected in epididymal spermatozoa and epithelial cells using combined laser microdissection/HPLC-ESI-MS analysis. In support, a substantial reduction of sialic acid residues bound to the surface of spermatozoa was documented in men with a recent history of E. coli-associated epididymitis. In vitro, such an UPEC induced N-acetylneuraminic acid release from human spermatozoa was effectively counteracted by a sialidase inhibitor. These findings strongly suggest a substantial remodeling of the glycocalyx of spermatozoa and epididymal epithelial cells by endogenous sialidases after a premature acrosome reaction during acute epididymitis.
- Published
- 2016
44. Developmental origins of male subfertility: role of infection, inflammation, and environmental factors
- Author
-
Undraga Schagdarsurengin, Andreas Meinhardt, Klaus Steger, and Patrick S. Western
- Subjects
Male ,0301 basic medicine ,Immunology ,Environment ,Biology ,Infections ,Germline ,Epigenesis, Genetic ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Risk Factors ,Testis ,Humans ,Immunology and Allergy ,Epigenetics ,Infertility, Male ,Epididymis ,Inflammation ,Genetics ,030219 obstetrics & reproductive medicine ,Gene Expression Regulation, Developmental ,Cell Differentiation ,Embryo ,Epigenome ,Cellular Reprogramming ,Chromatin ,Germ Cells ,030104 developmental biology ,Maternal Exposure ,Epiblast ,Prenatal Exposure Delayed Effects ,DNA methylation ,Female ,Gene-Environment Interaction ,Reprogramming ,Biomarkers - Abstract
Male gamete development begins with the specification of primordial cells in the epiblast of the early embryo and is not complete until spermatozoa mature in the epididymis of adult males. This protracted developmental process involves extensive alteration of the paternal germline epigenome. Initially, epigenetic reprogramming in fetal germ cells results in removal of most DNA methylation, including parent-specific epigenetic information. The germ cells then establish sex-specific epigenetic information through de novo methylation and undergo spermatogenesis. Chromatin in haploid germ cells is repackaged into protamines during spermiogenesis, providing further widespread epigenetic reorganization. Finally, after fertilization, epigenetic reprogramming in the preimplantation embryo is necessary for regaining totipotency. These events provide substantial windows during which epigenetic errors either may be corrected or may occur in the germline. There is now increasing evidence that environmental factors such as exposure to toxicants, the parents' and individual's diet, and even infectious and inflammatory events in the male reproductive tract may influence epigenetic reprogramming. This, together with other damage inflicted on the germline chromatin, may result in negative consequences for fertility and health. Large epidemiological birth cohort studies have yielded insight into possible causative environmental factors. Together with experimental animal studies, a clearer view of environmental impacts on fetal development and their intergenerational and even transgenerational effects on reproductive health has emerged and is reviewed in this article.
- Published
- 2016
45. Blocking Macrophage Migration Inhibitory Factor Protects Against Cisplatin-Induced Acute Kidney Injury in Mice
- Author
-
Philipp Lacher, Anping Xu, Patrick Ming-Kuen Tang, Jörg Klug, Xiao-Ru Huang, Andreas Meinhardt, Zhihua Zheng, Suada Fröhlich, Anna Aspesi, Lydie Da Costa, Pawel Szczęśniak, Christine Carlsson-Skwirut, Ying Tang, Hui-Yao Lan, Rujun Gong, Jun Lv, Jinhong Li, and Gunter Fingerle-Rowson
- Subjects
0301 basic medicine ,Ribosomal Proteins ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Apoptosis ,urologic and male genital diseases ,Kidney ,03 medical and health sciences ,Mice ,Necrosis ,Ribosomal protein S19 ,Drug Discovery ,Genetics ,medicine ,otorhinolaryngologic diseases ,Animals ,Humans ,Renal replacement therapy ,Molecular Biology ,Macrophage Migration-Inhibitory Factors ,Pharmacology ,Inflammation ,Mice, Knockout ,biology ,business.industry ,urogenital system ,Acute kidney injury ,Histocompatibility Antigens Class II ,NF-kappa B ,Interleukin ,Genetic Therapy ,Acute Kidney Injury ,medicine.disease ,female genital diseases and pregnancy complications ,Nitric oxide synthase ,Antigens, Differentiation, B-Lymphocyte ,Intramolecular Oxidoreductases ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Cancer research ,Molecular Medicine ,Tumor necrosis factor alpha ,Macrophage migration inhibitory factor ,Original Article ,Cisplatin ,business ,Signal Transduction - Abstract
Macrophage migration inhibitory factor (MIF) is elevated in patients with acute kidney injury (AKI) and is suggested as a potential predictor for renal replacement therapy in AKI. In this study, we found that MIF also plays a pathogenic role and is a therapeutic target for AKI. In a cisplatin-induced AKI mouse model, elevated plasma MIF correlated with increased serum creatinine and the severity of renal inflammation and tubular necrosis, whereas deletion of MIF protected the kidney from cisplatin-induced AKI by largely improving renal functional and histological injury, and suppressing renal inflammation including upregulation of cytokines such as interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), IL-6, inducible nitric oxide synthase (iNOS), MCP-1, IL-8, and infiltration of macrophages, neutrophils, and T cells. We next developed a novel therapeutic strategy for AKI by blocking the endogenous MIF with an MIF inhibitor, ribosomal protein S19 (RPS19). Similar to the MIF-knockout mice, treatment with RPS19, but not the mutant RPS19, suppressed cisplatin-induced AKI. Mechanistically, we found that both genetic knockout and pharmacological inhibition of MIF protected against AKI by inactivating the CD74-nuclear factor κB (NF-κB) signaling. In conclusion, MIF is pathogenic in cisplatin-induced AKI. Targeting MIF with an MIF inhibitor RPS19 could be a promising therapeutic potential for AKI.
- Published
- 2018
46. Ultra-structure of the sperm head-to-tail linkage complex in the absence of the spermatid-specific LINC component SPAG4
- Author
-
Andreas Meinhardt, Sigrid Hoyer-Fender, Kefei Yang, and Ibrahim M. Adham
- Subjects
0301 basic medicine ,Male ,Histology ,Spermatid ,Nuclear Proteins ,Cell Biology ,Biology ,Sperm ,Cell biology ,03 medical and health sciences ,Medical Laboratory Technology ,Mice ,030104 developmental biology ,medicine.anatomical_structure ,Centrosome ,Sperm Tail ,medicine ,Nuclear lamina ,Animals ,Sperm Head ,SUN domain ,Nuclear protein ,Nuclear membrane ,Cytoskeleton ,Molecular Biology - Abstract
Tight connection between sperm head and tail is crucial for the transport of the male genome and fertilization. The linkage complex, the sperm head-to-tail coupling apparatus (HTCA), originates from the centrosome and anchors to the nuclear membrane. In contrast to its ultra-structural organization, which is already well known for decades, its protein composition largely still awaits future deciphering. SUN-domain proteins are essential components of a complex that links the cytoskeleton to the peripheral nucleoskeleton, which is the nuclear lamina. Here, we studied the impact of the SUN protein SPAG4/SUN4 on the formation of the HTCA. SPAG4/SUN4 is specifically expressed in haploid male germ cells showing a polarized distribution towards the posterior pole in late spermatids that corresponds to the tail attachment site. SPAG4-deficient male mice are infertile with compromised manchette formation and malformed sperm heads. Nonetheless, sperm tails are present demonstrating dispensability of a proper manchette for their formation. Ultra-structural analyses revealed that the development of the sperm head-to-tail linkage complex in the absence of SPAG4 resembles that in the wild type. However, in SPAG4-deficient sperm, the attachment site is diminished with obvious lateral detachment of the HTCA from the nucleus. Our results thus indicate that SPAG4, albeit not essential for the formation of the HTCA per se, is, nevertheless, required for tightening the sperm head-to-tail anchorage by provoking the correct attachment of the lateral parts of the basal plate to the implantation fossa.
- Published
- 2018
47. Extracellular MIF, but not its homologue D-DT, promotes fibroblast motility independently of its receptor complex CD74/CD44
- Author
-
Suada Fröhlich, Pawel Szczęśniak, Jörg Klug, Henning Urlaub, Uwe Plessmann, Robert Grosse, Lin Leng, Andreas Meinhardt, Richard Bucala, and Tamara Henke
- Subjects
Receptor complex ,Chemokinesis ,Motility ,chemical and pharmacologic phenomena ,Biology ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Movement ,Caveolae ,Chlorocebus aethiops ,otorhinolaryngologic diseases ,Extracellular ,Animals ,Humans ,Macrophage Migration-Inhibitory Factors ,030304 developmental biology ,0303 health sciences ,Cell Membrane ,Histocompatibility Antigens Class II ,Cell Biology ,Fibroblasts ,Actin cytoskeleton ,3. Good health ,Cell biology ,Antigens, Differentiation, B-Lymphocyte ,HEK293 Cells ,Hyaluronan Receptors ,COS Cells ,NIH 3T3 Cells ,Macrophage migration inhibitory factor ,Intracellular ,030215 immunology ,Signal Transduction - Abstract
Macrophage migration inhibitory factor (MIF) and its homologue D-dopachrome tautomerase (D-DT) are ubiquitous, pro-inflammatory cytokines with chemokine-like functions that coordinate a wide spectrum of biological activities like migration. Here, we biotin-tagged intracellular MIF/D-DT in vivo to identify important cytosolic interactors and found a plethora of actin cytoskeleton-associated proteins. While the CD74/CD44 receptor complex is essential for signalling transduction in fibroblasts by extracellular MIF/D-DT, our interactome data rather suggested direct effects. We thus investigated whether MIF/D-DT can modulate cell migration independent of CD74/CD44. To differentiate between receptor- and non-receptor-mediated motility, we treated fibroblasts that are deficient in CD74 and CD44 or that express both proteins with recombinant MIF/D-DT. Interestingly, only MIF could stimulate chemokinesis in the presence or absence of CD74/CD44. The pro-migratory effects of MIF depended on lipid raft/caveolae-mediated but not clathrin-mediated endocytosis, on its tautomerase activity and, likely, on its thiol protein oxidoreductase activity. As MIF treatment restrained actin polymerisation in vitro our findings establish a new intracellular role for MIF/D-DT in driving cell motility by modulating the actin cytoskeleton.
- Published
- 2018
48. Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics
- Author
-
Sudhanshu Bhushan, Ming Wang, Tao Lei, Jörg Klug, Yongning Lu, Trinad Chakraborty, Andreas Meinhardt, Martin Bergmann, Ferial Aslani, Amir Rafiq, Monika Fijak, Zhengguo Zhang, and Sanjeev Kumar
- Subjects
0301 basic medicine ,Programmed cell death ,Virulence Factors ,urologic and male genital diseases ,medicine.disease_cause ,Biochemistry ,Virulence factor ,Histones ,03 medical and health sciences ,Hemolysin Proteins ,Necrosis ,Adenosine Triphosphate ,Genetics ,Extracellular ,medicine ,Escherichia coli ,HMGB1 Protein ,Molecular Biology ,Caspase ,Membrane Potential, Mitochondrial ,Innate immune system ,biology ,Cell Death ,Chemistry ,Escherichia coli Proteins ,Cell Membrane ,Hemolysin ,Cell biology ,Mitochondria ,030104 developmental biology ,Apoptosis ,biology.protein ,Calcium ,Reactive Oxygen Species ,Biotechnology - Abstract
Uropathogenic Escherichia coli (UPEC) is the most common cause of urinary tract infections. In this study, UPEC strains harboring hemolysin A (HlyA) did not induce programmed cell death pathways by the activation of caspases. Instead, the UPEC pore-forming toxin HlyA triggered an increase in mitochondrial Ca2+ levels and manipulated mitochondrial dynamics by causing fragmentation of the mitochondrial network. Alterations in mitochondrial dynamics resulted in severe impairment of mitochondrial functions by loss of membrane potential, increase in reactive oxygen species production, and ATP depletion. Moreover, HlyA caused disruption of plasma membrane integrity that was accompanied by extracellular release of the danger-associated molecules high-mobility group box 1 (HMGB1) and histone 3 (H3). Our results indicate that UPEC induced programmed cell necrosis by irreversibly impairing mitochondrial function. This finding suggests a strategy devised by UPEC at the onset of infection to escape early innate immune response and silently propagate inside host cells.-Lu, Y., Rafiq, A., Zhang, Z., Aslani, F., Fijak, M., Lei, T., Wang, M., Kumar, S., Klug, J., Bergmann, M., Chakraborty, T., Meinhardt, A., Bhushan, S. Uropathogenic Escherichia coli virulence factor hemolysin A causes programmed cell necrosis by altering mitochondrial dynamics.
- Published
- 2018
49. Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells
- Author
-
Nelli Baal, Florian Eisel, Magdalena Walecki, Jörg Klug, Holger Hackstein, Andreas Meinhardt, Monika Fijak, Eva Wahle, and Agnieszka Paradowska-Dogan
- Subjects
Adult ,Male ,medicine.medical_specialty ,Cellular differentiation ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Foxp3 expression ,Internal medicine ,medicine ,Humans ,IL-2 receptor ,Molecular Biology ,Regulation of gene expression ,HEK 293 cells ,FOXP3 ,Cell Differentiation ,Forkhead Transcription Factors ,hemic and immune systems ,Articles ,Cell Biology ,Middle Aged ,Signaling ,Cell biology ,Androgen receptor ,HEK293 Cells ,Endocrinology ,Gene Expression Regulation ,Receptors, Androgen ,Female ,Homeostasis - Abstract
CD4+CD25+Foxp3+ Treg cells are crucial for the maintenance of immunological homeostasis. Androgens significantly induce Foxp3 expression in humans and regulate the differentiation of Treg cells. A functional androgen receptor–binding site is identified within the Foxp3 locus leading to epigenetic changes of histone H4., CD4+CD25+Foxp3+ regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-β and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells.
- Published
- 2015
50. UropathogenicEscherichia coli(UPEC) induced antimicrobial gene expression in the male reproductive tract of rat: evaluation of the potential of Defensin 21 to limit infection
- Author
-
Shashi Bhushan, Andreas Meinhardt, Angireddy Rajesh, Suresh Yenugu, Barnali Biswas, S. K. Suraj, and Y. Lu
- Subjects
Male ,medicine.drug_class ,Urology ,Endocrinology, Diabetes and Metabolism ,Antimicrobial peptides ,Antibiotics ,Gene Expression ,Genitalia, Male ,Biology ,medicine.disease_cause ,Microbiology ,Defensins ,Endocrinology ,Antibiotic resistance ,medicine ,Animals ,Uropathogenic Escherichia coli ,Rats, Wistar ,Escherichia coli ,Defensin ,Pathogen ,Antimicrobial ,Epididymis ,Virology ,Rats ,medicine.anatomical_structure ,Reproductive Medicine - Abstract
Summary Escherichia coli (E. coli) is a common pathogen in epididymitis, which represents a prevalent entity in male reproductive tract infections (RTI). Although current treatment regimens using antibiotics are satisfactory, development of antimicrobial resistance by the pathogen represents a challenge in the management of RTI. Hence, identification of antimicrobial peptides as alternatives to antibiotics has gained importance. We demonstrate that in a rat epididymo-orchitis model induced with uropathogenic E. coli (UPEC) strain MTCC 729, the expression of defensins and defensin-like Spag11 genes are induced in the epididymis and testes. The induction of antimicrobial gene expression is paralleled by phosphorylation of the NF-kB subunit p65 and the inhibitor of NFkB (IkB-alpha), decreased levels of histone deacetylase 1 and increased methylation of Histone 3, indicating the role of classical Toll-like receptor mediated signaling and epigenetic regulation. Recombinant Defensin 21, when administered to UPEC-infected rats, substantially reduced the bacterial load in the epididymis and testis and proved to be more effective than gentamycin. The ability of Defensin 21 to limit RTI provides support that antibacterial proteins of the male reproductive tract may be used as potential alternatives to antibiotics in treatment of this disease.
- Published
- 2015
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.