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1. Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids

Author

Auger, Jean-Philippe, Zimmermann, Max, Faas, Maria, Stifel, Ulrich, Chambers, David, Krishnacoumar, Brenda, Taudte, R. Verena, Grund, Charlotte, Erdmann, Gitta, Scholtysek, Carina, Uderhardt, Stefan, Ben Brahim, Oumaima, Pascual Maté, Mónica, Stoll, Cornelia, Böttcher, Martin, Palumbo-Zerr, Katrin, Mangan, Matthew S. J., Dzamukova, Maria, Kieler, Markus, Hofmann, Melanie, Blüml, Stephan, Schabbauer, Gernot, Mougiakakos, Dimitrios, Sonnewald, Uwe, Hartmann, Fabian, Simon, David, Kleyer, Arnd, Grüneboom, Anika, Finotto, Susetta, Latz, Eicke, Hofmann, Jörg, Schett, Georg, Tuckermann, Jan, and Krönke, Gerhard

Published
2024
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2. Metabolic support by macrophages sustains colonic epithelial homeostasis

Author

Fritsch, Stephanie Deborah, Sukhbaatar, Nyamdelger, Gonzales, Karine, Sahu, Alishan, Tran, Loan, Vogel, Andrea, Mazic, Mario, Wilson, Jayne Louise, Forisch, Stephan, Mayr, Hannah, Oberle, Raimund, Weiszmann, Jakob, Brenner, Martin, Vanhoutte, Roeland, Hofmann, Melanie, Pirnes-Karhu, Sini, Magnes, Christoph, Kühnast, Torben, Weckwerth, Wolfram, Bock, Christoph, Klavins, Kristaps, Hengstschläger, Markus, Moissl-Eichinger, Christine, Schabbauer, Gernot, Egger, Gerda, Pirinen, Eija, Verhelst, Steven H.L., and Weichhart, Thomas

Published
2023
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3. The human placenta shapes the phenotype of decidual macrophages

Author

Vondra, Sigrid, Höbler, Anna-Lena, Lackner, Andreas Ian, Raffetseder, Johanna, Mihalic, Zala Nikita, Vogel, Andrea, Saleh, Leila, Kunihs, Victoria, Haslinger, Peter, Wahrmann, Markus, Husslein, Heinrich, Oberle, Raimund, Kargl, Julia, Haider, Sandra, Latos, Paulina, Schabbauer, Gernot, Knöfler, Martin, Ernerudh, Jan, and Pollheimer, Jürgen

Published
2023
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4. Platelet p110β mediates platelet-leukocyte interaction and curtails bacterial dissemination in pneumococcal pneumonia

Author

Schrottmaier, Waltraud Cornelia, Kral-Pointner, Julia Barbara, Salzmann, Manuel, Mussbacher, Marion, Schmuckenschlager, Anna, Pirabe, Anita, Brunnthaler, Laura, Kuttke, Mario, Maier, Barbara, Heber, Stefan, Datler, Hannes, Ekici, Yasemin, Niederreiter, Birgit, Heber, Ulrike, Blomgren, Bo, Gorki, Anna-Dorothea, Söderberg-Nauclér, Cecilia, Payrastre, Bernard, Gratacap, Marie-Pierre, Knapp, Sylvia, Schabbauer, Gernot, and Assinger, Alice

Published
2022
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6. The PI3K pathway preserves metabolic health through MARCO-dependent lipid uptake by adipose tissue macrophages

Author

Brunner, Julia S., Vogel, Andrea, Lercher, Alexander, Caldera, Michael, Korosec, Ana, Pühringer, Marlene, Hofmann, Melanie, Hajto, Alexander, Kieler, Markus, Garrido, Lucia Quemada, Kerndl, Martina, Kuttke, Mario, Mesteri, Ildiko, Górna, Maria W., Kulik, Marta, Dominiak, Paulina M., Brandon, Amanda E., Estevez, Emma, Egan, Casey L., Gruber, Florian, Schweiger, Martina, Menche, Jörg, Bergthaler, Andreas, Weichhart, Thomas, Klavins, Kristaps, Febbraio, Mark A., Sharif, Omar, and Schabbauer, Gernot

Published
2020
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10. Bona fide dendritic cells are pivotal precursors for osteoclasts.

Author

Puchner, Antonia, Simader, Elisabeth, Saferding, Victoria, Hofmann, Melanie, Kieler, Markus, Brunner, Julia, Pfeifle, René, Niederreiter, Birgit, Krönke, Gerhard, Schabbauer, Gernot, Georgel, Philippe, Diehl, Gretchen, Steiner, Guenter, Hayer, Silvia, Redlich, Kurt, Smolen, Josef S., Aletaha, Daniel, and Blüml, Stephan

Published
2024
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12. Environmental arginine controls multinuclear giant cell metabolism and formation

Author

Brunner, Julia S., Vulliard, Loan, Hofmann, Melanie, Kieler, Markus, Lercher, Alexander, Vogel, Andrea, Russier, Marion, Brüggenthies, Johanna B., Kerndl, Martina, Saferding, Victoria, Niederreiter, Birgit, Junza, Alexandra, Frauenstein, Annika, Scholtysek, Carina, Mikami, Yohei, Klavins, Kristaps, Krönke, Gerhard, Bergthaler, Andreas, O’Shea, John J., Weichhart, Thomas, Meissner, Felix, Smolen, Josef S., Cheng, Paul, Yanes, Oscar, Menche, Jörg, Murray, Peter J., Sharif, Omar, Blüml, Stephan, and Schabbauer, Gernot

Published
2020
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15. Therapeutic Modulation of Plasmacytoid Dendritic Cells in Experimental Arthritis

Author

Nehmar, Ramzi, Alsaleh, Ghada, Voisin, Benjamin, Flacher, Vincent, Mariotte, Alexandre, Saferding, Victoria, Puchner, Antonia, Niederreiter, Birgit, Vandamme, Thierry, Schabbauer, Gernot, Kastner, Philippe, Chan, Susan, Kirstetter, Peggy, Holcmann, Martin, Mueller, Christopher, Sibilia, Jean, Bahram, Seiamak, Blüml, Stephan, and Georgel, Philippe

Published
2017
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22. WAVE1 mediates suppression of phagocytosis by phospholipid-derived DAMPs

Author

Matt, Ulrich, Sharif, Omar, Martins, Rui, Furtner, Tanja, Langeberg, Lorene, Gawish, Riem, Elbau, Immanuel, Zivkovic, Ana, Lakovits, Karin, Oskolkova, Olga, Doninger, Bianca, Vychytil, Andreas, Perkmann, Thomas, Schabbauer, Gernot, Binder, Christoph J., Bochkov, Valery N., Scott, John D., and Knapp, Sylvia

Subjects
Binding proteins -- Health aspects, Immune response -- Research, Phagocytosis -- Research, Health care industry
Abstract

Clearance of invading pathogens is essential to preventing overwhelming inflammation and sepsis that are symptomatic of bacterial peritonitis. Macrophages participate in this innate immune response by engulfing and digesting pathogens, [...]

Published
2013
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25. Determination of Extravasation Effects of Nal-Iri and Trabectedin and Evaluation of Treatment Options for Trabectedin Extravasation in a Preclinical Animal Model.

Author

Keritam, Omar, Juhasz, Viktoria, Schöfer, Christian, Thallinger, Christiane, Aretin, Marie-Bernadette, Schabbauer, Gernot, Breuss, Johannes, Unseld, Matthias, and Uhrin, Pavel

Subjects
TRABECTEDIN, TACROLIMUS, EXTRAVASATION, ANIMAL models in research, SUBCUTANEOUS injections, IRINOTECAN
Abstract

Background: Extravasation during chemotherapy administration can lead to dangerous adverse effects ranging from pain to tissue necrosis. Evidence-based data about prevention and treatment of extravasation injuries of some clinically used compounds still remains elusive. This work aimed to investigate, in a preclinical mouse model, the effects of extravasation of two chemotherapeutic agents, nanoliposomal irinotecan (nal-Iri) and trabectedin. In addition, we aimed to study treatment options for injuries induced by extravasation of these substances. Methods: Mice were subcutaneously injected with nal-Iri or trabectedin applied in clinically used concentration. Doxorubicin was used as a positive control. In subsequently performed experiments, hyaluronidase, DMSO and tacrolimus were tested as potential treatments against extravasation-induced injuries by trabectedin. Systemic effects were analyzed by observation and documentation of the health status of mice and local reactions were measured and graded. In addition, hematoxylin-eosin stained histological sections of the treated skin areas were analyzed. Results: Of the two tested substances, only trabectedin showed vesicant effects. Subcutaneous injection of trabectedin caused erythema formation in mice by day two that was progressing to skin ulcerations by day five. Furthermore, we found that topical treatment of mice with tacrolimus or DMSO reduced the vesicant effects of trabectedin. The results observed in vivo were supported microscopically by the analysis of histological sections. Conclusions: We recommend classifying trabectedin as a vesicant agent and nal-Iri as a non-vesicant agent. Furthermore, our results obtained in a preclinical model suggest that tacrolimus and DMSO might be suitable treatment options of trabectedin extravasations, a finding that might be further utilized in clinical studies. [ABSTRACT FROM AUTHOR]

Published
2022
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26. OS-024-YI - Scavenger receptor MARCO is associated with an immunosuppressive microenvironment and tumor progression in intrahepatic cholangiocarcinoma

Author

Lizaso, Aloña Agirre, Izagirre, Maider Huici, Rourke, Colm O, Zhuravleva, Ekaterina, Korosec, Ana, Azkargorta, Mikel, Elortza, Felix, Ilyas, Sumera I., Gores, Gregory, Andersen, Jesper, Schabbauer, Gernot, Bujanda, Luis, Rodrigues, Pedro Miguel, Sharif, Omar, Banales, Jesus Maria, and Perugorria, María Jesús

Published
2023
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27. SCAVENGER RECEPTOR MARCO IS ASSOCIATED WITH AN IMMUNOSUPPRESSIVE MICROENVIRONMENT AND TUMOR PROGRESSION IN INTRAHEPATIC CHOLANGIOCARCINOMA

Author

Agirre-Lizaso, Aloña, Huici-Izagirre, Maider, O’Rourke, Colm J., Zhuravleva, Ekaterina, Korosec, Ana, Azkargorta, Mikel, Elortza, Felix, Vaquero, Javier, Ilyas, Sumera I., Gores, Gregory J., Andersen, Jesper B., Schabbauer, Gernot, Bujanda, Luis, Rodrigues, Pedro M., Sharif, Omar, Banales, Jesus M., and Perugorria, Maria J.

Published
2023
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28. PI3K Signaling in Dendritic Cells Aggravates DSS-Induced Colitis.

Author

Kuttke, Mario, Hromadová, Dominika, Yildirim, Ceren, Brunner, Julia S., Vogel, Andrea, Paar, Hannah, Peters, Sophie, Weber, Maria, Hofmann, Melanie, Kerndl, Martina, Kieler, Markus, Datler, Hannes, Musiejovsky, Laszlo, Salzmann, Manuel, Lang, Michaela, Soukup, Klara, Halfmann, Angela, Sharif, Omar, and Schabbauer, Gernot

Subjects
DENDRITIC cells, COLITIS, INFLAMMATORY bowel diseases, PHOSPHATIDYLINOSITOL 3-kinases, PATHOLOGY
Abstract

Aberrant innate immune responses to the gut microbiota are causally involved in the pathogenesis of inflammatory bowel diseases (IBD). The exact triggers and main signaling pathways activating innate immune cells and how they modulate adaptive immunity in IBD is still not completely understood. Here, we report that the PI3K/PTEN signaling pathway in dendritic cells enhances IL-6 production in a model of DSS-induced colitis. This results in exacerbated Th1 cell responses and increased mortality in DC-specific PTEN knockout (PTENΔDC) animals. Depletion of the gut microbiota using antibiotics as well as blocking IL-6R signaling rescued mortality in PTENΔDC mice, whereas adoptive transfer of Flt3L-derived PTEN-/- DCs into WT recipients exacerbated DSS-induced colitis and increased mortality. Taken together, we show that the PI3K signaling pathway in dendritic cells contributes to disease pathology by promoting IL-6 mediated Th1 responses. [ABSTRACT FROM AUTHOR]

Published
2022
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29. An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia.

Author

Hao Xie, Heier, Christoph, Xia Meng, Bakiri, Latifa, Pototschnig, Isabella, Zhiyuan Tang, Schauer, Silvia, Baumgartner, Vanessa J., Grabner, Gernot F., Schabbauer, Gernot, Wolinski, Heimo, Robertson, Graham R., Hoefler, Gerald, Wenwen Zeng, Wagner, Erwin F., Schweiger, Martina, and Zechner, Rudolf

Subjects
BROWN adipose tissue, CACHEXIA, WHITE adipose tissue, ADIPOSE tissues, NEURONS
Abstract

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)–deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophagesympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients. [ABSTRACT FROM AUTHOR]

Published
2022
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34. Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages.

Author

Sharif, Omar, Brunner, Julia Stefanie, Korosec, Ana, Martins, Rui, Jais, Alexander, Snijder, Berend, Vogel, Andrea, Caldera, Michael, Hladik, Anastasiya, Lakovits, Karin, Saluzzo, Simona, Boehm, Benedikta, Gorki, Anna-Dorothea, Mesteri, Ildiko, Lindroos-Christensen, Josefine, Tillmann, Katharina, Stoiber, Dagmar, Menche, Jörg, Schabbauer, Gernot, and Bilban, Martin

Subjects
INSULIN sensitivity, WHITE adipose tissue, ADIPOSE tissues, INSULIN resistance, MYELOID cells, LEPTIN
Abstract

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell-expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health. [ABSTRACT FROM AUTHOR]

Published
2021
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37. TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms.

Author

Esparza-Baquer, Aitor, Labiano, Ibone, Sharif, Omar, Agirre-Lizaso, Aloña, Oakley, Fiona, Rodrigues, Pedro M., Zhuravleva, Ekaterina, O'Rourke, Colm J., Hijona, Elizabeth, Jimenez-Agüero, Raul, Riaño, Ioana, Landa, Ana, La Casta, Adelaida, Zaki, Marco Y. W., Munoz-Garrido, Patricia, Azkargorta, Mikel, Elortza, Felix, Vogel, Andrea, Schabbauer, Gernot, and Aspichueta, Patricia

Subjects
FIBROSIS, HEPATOCELLULAR carcinoma, ALPHA fetoproteins, MEDICAL sciences, MEDICAL research, LIVER, MYELOID differentiation factor 88, GENOME-wide association studies
Published
2021
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38. More than just protein building blocks: how amino acids and related metabolic pathways fuel macrophage polarization.

Author

Kieler, Markus, Hofmann, Melanie, and Schabbauer, Gernot

Subjects
AMINO acids, MACROPHAGES, GLUTAMINE, AMINO acid metabolism, PROTEINS, HOMEOSTASIS, IMMUNE response
Abstract

Macrophages represent the first line of defence in innate immune responses and additionally serve important functions for the regulation of host inflammation and tissue homeostasis. The M1/M2 model describes the two extremes of macrophage polarization states, which can be induced by multiple stimuli, most notably by LPS/IFN‐γ and IL‐4/IL‐13. Historically, the expression of two genes encoding for enzymes, which use the same amino acid as their substrate, iNOS and ARG1, has been used to define classically activated M1 (iNOS) and alternatively activated M2 (ARG1) macrophages. This 'arginine dichotomy' has recently become a matter of debate; however, in parallel with the emerging field of immunometabolism there is accumulating evidence that these two enzymes and their related metabolites are fundamentally involved in the intrinsic regulation of macrophage polarization and function. The aim of this review is to highlight recent advances in macrophage biology and immunometabolism with a specific focus on amino acid metabolism and their related metabolic pathways: iNOS/ARG1 (arginine), TCA cycle and OXPHOS (glutamine) as well as the one‐carbon metabolism (serine, glycine). [ABSTRACT FROM AUTHOR]

Published
2021
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40. microRNA‐146a controls age‐related bone loss.

Author

Saferding, Victoria, Hofmann, Melanie, Brunner, Julia S., Niederreiter, Birgit, Timmen, Melanie, Magilnick, Nathaniel, Hayer, Silvia, Heller, Gerwin, Steiner, Günter, Stange, Richard, Boldin, Mark, Schabbauer, Gernot, Weigl, Moritz, Hackl, Matthias, Grillari, Johannes, Smolen, Josef S., and Blüml, Stephan

Subjects
OSTEOPOROSIS, BONES, BONE growth, WNT signal transduction, BONE marrow, LIFE spans
Abstract

Bone loss is one of the consequences of aging, leading to diseases such as osteoporosis and increased susceptibility to fragility fractures and therefore considerable morbidity and mortality in humans. Here, we identify microRNA‐146a (miR‐146a) as an essential epigenetic switch controlling bone loss with age. Mice deficient in miR‐146a show regular development of their skeleton. However, while WT mice start to lose bone with age, animals deficient in miR‐146a continue to accrue bone throughout their life span. Increased bone mass is due to increased generation and activity of osteoblasts in miR‐146a‐deficient mice as a result of sustained activation of bone anabolic Wnt signaling during aging. Deregulation of the miR‐146a target genes Wnt1 and Wnt5a parallels bone accrual and osteoblast generation, which is accompanied by reduced development of bone marrow adiposity. Furthermore, miR‐146a‐deficient mice are protected from ovariectomy‐induced bone loss. In humans, the levels of miR‐146a are increased in patients suffering fragility fractures in comparison with those who do not. These data identify miR‐146a as a crucial epigenetic temporal regulator which essentially controls bone homeostasis during aging by regulating bone anabolic Wnt signaling. Therefore, miR‐146a might be a powerful therapeutic target to prevent age‐related bone dysfunctions such as the development of bone marrow adiposity and osteoporosis. [ABSTRACT FROM AUTHOR]

Published
2020
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41. Reduced DICER1 Expression Bestows Rheumatoid Arthritis Synoviocytes Proinflammatory Properties and Resistance to Apoptotic Stimuli

Author

Alsaleh, Ghada, Nehmar, Ramzi, Blüml, Stephan, Schleiss, Cédric, Ostermann, Eleonore, Dillenseger, Jean-Philippe, Sayeh, Amira, Choquet, Philippe, Dembélé, Doulaye, François, Antoine, Salmon, Jean-Hugues, Paul, Nicodème, Schabbauer, Gernot, Bierry, Guillaume, Meyer, Alain, Gottenberg, Jacques-Eric, Haas, Gabrielle, Pfeffer, Sébastien, Vallat, Laurent, Sibilia, Jean, Bahram, Seiamak, Georgel, Philippe, Physiopathologie des arthrites, Université Louis Pasteur - Strasbourg I, Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie Préclinique-UF6237, Pôle d'imagerie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Reims (CHU Reims), Service de neuroradiologie [Lille], Hôpital Roger Salengro [Lille]-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Rheumatology [CHU Strasbourg], CHU Strasbourg, Architecture et Réactivité de l'ARN (ARN), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Immunologie cellulaire et tissulaire, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR113-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de rhumatologie [Strasbourg], and CHU Strasbourg-Hôpital de Hautepierre [Strasbourg]

Subjects
Inflammation, Ribonuclease III, [SDV]Life Sciences [q-bio], Physique [physics]/Mécanique [physics], Apoptosis, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Synoviocytes, Arthritis, Rheumatoid, DEAD-box RNA Helicases, Mice, Sciences du Vivant [q-bio]/Autre [q-bio.OT], Gene Expression Regulation, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

OBJECTIVE: While the regulatory role of individual microRNAs (miRNAs) in rheumatoid arthritis (RA) is well established, the role of DICER1 in the pathogenesis of the disease has not yet been investigated. The purpose of this study was to analyze the expression of factors involved in miRNA biogenesis in fibroblast-like synoviocytes (FLS) from RA patients and to monitor the arthritis triggered by K/BxN serum transfer in mice deficient in the Dicer gene (Dicer(d/d) ). METHODS: The expression of genes and precursor miRNAs was quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). MicroRNA macroarray profiling was monitored by qRT-PCR. Cytokines were quantified by enzyme-linked immunosorbent assay. Experimental arthritis in mice was achieved by the transfer of serum from K/BxN donors. Apoptosis was quantified using an enzyme-linked immunosorbent assay. RESULTS: We found decreased DICER1 and mature miRNA expression in synovial fibroblasts from RA patients. These cells were hyperresponsive to lipopolysaccharide, as evidenced by their increased interleukin-6 secretion upon stimulation. Experimental serum-transfer arthritis in Dicer(d/d) mice confirmed that an unbalanced biogenesis of miRNAs correlated with an enhanced inflammatory response. Synoviocytes from both RA patients and Dicer(d/d) mice exhibited increased resistance to apoptotic stimuli. CONCLUSION: The findings of this study further substantiate the important role of DICER1 in the maintenance of homeostasis and the regulation of inflammatory responses.

Published
2016

42. Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways

Author

Kral, Julia Barbara, Kuttke, Mario, Schrottmaier, Waltraud Cornelia, Birnecker, Birgit, Warszawska, Joanna, Wernig, Christina, Paar, Hannah, Salzmann, Manuel, Sahin, Emine, Brunner, Julia Stefanie, Österreicher, Christoph, Knapp, Sylvia, Assinger, Alice, and Schabbauer, Gernot

Subjects
Article
Abstract

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTENMyKO), after induction of BIPF, exhibit increased TGF-β1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTENMyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTENMyKO mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.

Published
2016
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44. Macrophage PTEN Regulates Expression and Secretion of Arginase I Modulating Innate and Adaptive Immune Responses

Author

Sahin, Emine, Haubenwallner, Stefan, Kuttke, Mario, Kollmann, Isabella, Halfmann, Angela, Dohnal, Alexander B., Chen, Li, Cheng, Paul, Hoesel, Bastian, Einwallner, Elisa, Brunner, Julia, Kral, Julia B., Schrottmaier, Waltraud C., Thell, Kathrin, Saferding, Victoria, Blüml, Stephan, and Schabbauer, Gernot

Subjects
CD4-Positive T-Lymphocytes, Lipopolysaccharides, STAT3 Transcription Factor, Genotype, Mice, Transgenic, Adaptive Immunity, Immune Regulation, Mice, Phosphatidylinositol 3-Kinases, Animals, Humans, Myeloid Cells, RNA, Messenger, Cells, Cultured, Phosphoinositide-3 Kinase Inhibitors, Inflammation, Arginase, Interleukin-6, Tumor Necrosis Factor-alpha, CCAAT-Enhancer-Binding Protein-beta, Macrophages, Toll-Like Receptors, PTEN Phosphohydrolase, Immunity, Innate, Interleukin-10, Mice, Inbred C57BL, HEK293 Cells, Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating), Signal Transduction
Abstract

The activation of innate immune cells triggers numerous intracellular signaling pathways, which require tight control to mount an adequate immune response. The PI3K signaling pathway is intricately involved in innate immunity, and its activation dampens the expression and release of proinflammatory cytokines in myeloid cells. These signaling processes are strictly regulated by the PI3K antagonist, the lipid phosphatase, PTEN, a known tumor suppressor. Importantly, PTEN is responsible for the elevated production of cytokines such as IL-6 in response to TLR agonists, and deletion of PTEN results in diminished inflammatory responses. However, the mechanisms by which PI3K negatively regulates TLR signaling are only partially resolved. We observed that Arginase I expression and secretion were markedly induced by PTEN deletion, suggesting PTEN(-/-) macrophages were alternatively activated. This was mediated by increased expression and activation of the transcription factors C/EBPβ and STAT3. Genetic and pharmacologic experimental approaches in vitro, as well as in vivo autoimmunity models, provide convincing evidence that PI3K/PTEN-regulated extracellular Arginase I acts as a paracrine regulator of inflammation and immunity.

Published
2014

45. Cyclotides Suppress Human T-Lymphocyte Proliferation by an Interleukin 2-Dependent Mechanism

Author

Gründemann, Carsten, Thell, Kathrin, Lengen, Karin, Garcia-Käufer, Manuel, Huang, Yen-Hua, Huber, Roman, Craik, David J., Schabbauer, Gernot, and Gruber, Christian W.

Subjects
lymphocytes, cyclotide, immunosuppression, proliferation, T-Lymphocytes, lcsh:R, lcsh:Medicine, plant, Cyclotides, Rubiaceae, Lymphocyte Activation, peptide, cytokine, Leukocytes, Mononuclear, Humans, Interleukin-2, lcsh:Q, lcsh:Science, Cells, Cultured, Research Article, Cell Proliferation
Abstract

Cyclotides are a diverse and abundant group of ribosomally synthesized plant peptides containing a unique cyclic cystine-knotted topology that confers them with remarkable stability. Kalata B1, a representative member of this family of mini-proteins, has been found to inhibit the proliferation of human peripheral blood mononuclear cells. Analysis of T-cell proliferation upon treatment with chemically synthesized kalata B1 mutants revealed a region comprising inter-cysteine loops 1 and 2 of the cyclotide framework to be important for biological activity. Cytokine signaling analysis using an 'active' kalata B1 mutant [T20K], and the reference drug cyclosporin A (CsA) demonstrated that treatment of activated T-lymphocytes with these compounds decreased the expression of the interleukin-2 (IL-2) surface receptor as well as IL-2 cytokine secretion and IL-2 gene expression, whereas the 'inactive' kalata B1 mutant [V10K] did not cause any effects. The anti-proliferative activity of [T20K] kalata B1 was antagonized by addition of exogenous IL-2. Furthermore, treatment with [T20K] kalata B1 led to an initial reduction of the effector function, as indicated by the reduced IFN-γ and TNF-α production, but the levels of both cytokines stabilized over time and returned to their normal levels. On the other hand, the degranulation activity remained reduced. This indicated that cyclotides interfere with T-cell polyfunctionality and arrest the proliferation of immune-competent cells through inhibiting IL-2 biology at more than one site. The results open new avenues to utilize native and synthetically-optimized cyclotides for applications in immune-related disorders and as immunosuppressant peptides.

Published
2013

48. In vivo Tube Assay: An Optimised Protocol of the Directed in vivoAngiogenesis Assay by Implementing Immunohistochemistry.

Author

Unseld, Matthias, Breuss, Johannes M., Pausz, Clemens, Pablik, Eleonore, Schabbauer, Gernot, Zielinski, Christoph C., Uhrin, Pavel, and Prager, Gerald W.

Subjects
NEOVASCULARIZATION, IMMUNOHISTOCHEMISTRY, FLUORIMETRY, VASCULAR endothelial growth factors, ENDOTHELIAL cells
Abstract

Background: Angiogenesis, the formation of new blood vessels, is an essential process under physiological and pathological conditions. Method: Here, we improved the directed in vivo angiogenesis assay (DIVAA®) test, which is based on the usage of small Matrigel-filled tubes that are implanted into mice subcutaneously for a period of up to 15 days. The subsequent ex vivo assessment of neoangiogenesis within the silicon tubes is then achieved by fluorometry. Results: We showed that the immunohistochemical quantification of the ingrowth of endothelial cells, based on CD31, was superior to the fluorometric quantification advised in the manufacturer's instructions. We optimised the explantation procedure, ensuring the complete recovery of the ingrown vessels. Using this modified protocol, we investigated the effect of the length of stay of the implanted tubes as well as of the concentration of the growth factors VEGF and FGF on the assay. Conclusion: Our improved protocol offered an effective and reliable alternative to the original assay, which is expected to facilitate in vivo research on angiogenesis and, thus, might drive the development of novel therapeutic agents. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Published
2015
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