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• MR analysis reveals causal links between systemic cytokines and six common inflammatory skin diseases. • Ten cytokines identified as risk or protective factors for certain skin diseases. • Cytokine levels may serve as biomarkers for skin disease prediction and treatment. Previous observational studies have reported that systemic cytokines are associated with the risk of inflammatory skin diseases, but their conclusions remain controversial. We conducted a two-sample Mendelian randomization analysis to assess the relationship between systemic cytokines and six inflammatory skin disorders (including alopecia areata (AA), acne, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis (PS) and vitiligo), based on datasets from EArly Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium, acne GWAS conducted by Maris Teder Laving et al., IEU Open GWAS, and FinnGen database. Inverse-variance weighted (IVW) method was conducted in primary MR analysis, and supplemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO. By integrating the findings from both primary and sensitivity analyses, we identified ten systemic cytokines linked to the risk of six skin diseases using the IVW method. Briefly, four cytokines increased the risk of corresponding skin diseases: β-nerve growth factor (β-NGF) to AA (p = 0.005) and HS (p = 0.001), interleukin-8 (p = 0.014) to acne; interleukin-5 (p = 0.042) to AD; interleukin-13 (p = 0.049) to PS. In the meantime, seven cytokines could have protective effect on specific skin diseases: interleukin-9 (p = 0.040) and interleukin-2 receptor subunit alpha (IL-2ra) (p = 0.020) on AA; macrophage inflammatory protein (MIP)-1β (p = 0.020) on acne; monokine induced by IFN-γ (p = 0.006) on AD; interleukin-16 (p = 0.038), MIP-1β (p = 0.017) and IL-2ra (p = 0.020) on PS. This study reveals 13 causal associations between systemic cytokines and 6 skin diseases, offering new perspectives on the prevention and management of widespread inflammatory skin disorders. [ABSTRACT FROM AUTHOR]

Bacterial vaginosis (BV), characterized by an imbalance in the vaginal microbiota, is a prevalent condition among women of reproductive age and a risk factor for human immunodeficiency virus, sexually transmitted infections, and preterm birth. BV is generally considered to induce mucosal inflammation, but the specific pathways and cell types involved are not well characterized. This prospective study aimed to assess associations between microbial changes and mucosal immune responses in BV patients. Therefore, samples from 20 premenopausal women with BV and treated with metronidazole were analyzed. Vaginal swabs, menstrual cup, and endocervical cytobrush samples were collected before treatment, weekly for four weeks, and at 2, 4, and 6 months for Nugent scoring, immune cell populations and cytokine analysis. Of 105 study intervals, 27 (25.7%) showed improvement in Nugent category, 61 (58.1%) remained unchanged, and 17 (16.2%) worsened. Improvement correlated with decreased monocytes (p = 0.005), while worsening was linked to increased monocytes (p < 0.001) and dendritic cells (p = 0.02). B cells (p = 0.02) and IFN-γ-induced chemokines - IP-10 (p = 0.007), MIG (p = 0.049), and ITAC (p = 0.005) - were associated with improvement. In conclusion, although the T-cell-associated chemokines IP-10, ITAC, and MIG were strongly associated with improvements in Nugent category, our findings indicate that antigen-presenting cells, particularly monocytes, show the most dynamic response to shifts in the vaginal microbiota in patients with BV. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to use Mendelian randomisation to identify the causal relationship between a spectrum of 41 inflammatory cytokines and the development of oropharyngeal cancer. Methods: This study investigated genetic variants that have been associated with oral and oropharyngeal cancer using data from a large GWAS. Inflammatory cytokine data were obtained from 8293 asymptomatic individuals. The study primarily used inverse variance weighted and MR-Egger methods to determine the causal relationship between inflammatory cytokines and cancer incidence, complemented by a series of sensitivity analyses including MR-Egger, simple mode, weighted mode, weighted median and leave-one-out approaches. Results: Our study demonstrates that higher levels of interleukin-7 (IL-7) and interleukin-5 (IL-5) slightly increase the odds of oropharyngeal cancer by 0.07% [OR: 1.0007, p = 0.005] and 0.04% [OR: 1.0004, p = 0.015], corresponding to a modest increase. Similarly, increased PDGF-bb and CTACK levels are modestly associated with increased odds of oral and oropharyngeal cancer by 0.22% [OR: 1.0022, p = 0.031] and 0.17% [OR: 1.0017, p = 0.043], respectively. Conclusion: This investigation posits that IL-5 and IL-7 may be pertinent factors in the etiology of Oropharyngeal cancer, while PDGF bb and CTACK are likely implicated in the pathogenesis of both oral and oropharyngeal cancers. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha (TNF-α) is a significant cytokine that regulates bone resorption under inflammatory conditions. However, its mechanism of action in osteocytes remains unclear. In this study, highly purified osteocytes were isolated from dentin matrix protein 1 (DMP1)-Topaz mice using cell sorter. RNA sequencing (RNA-seq) revealed that TNF-α stimulation increased C-X-C motif chemokine ligand 10 (CXCL10) gene expression in osteocytes. Although CXCL10 did not affect osteoclast differentiation in vitro, it enhanced the migration of osteoclast precursors. Additionally, in the transwell co-culture system, TNF-α induced the migration of osteoclast precursors. However, this effect was attenuated by a CXCL10-neutralizing antibody. In vivo, mice were administered supracalvarial injections of TNF-α with or without the CXCL10-neutralizing antibody for 5 days. The percentage of CXCL10-positive osteocytes increased after TNF-α administration. Additionally, osteoclast formation and bone resorption were assessed. CXCL10-neutralizing antibody-treated calvariae exhibited a significantly lower number of osteoclasts and bone resorption than those treated with TNF-α alone. These results indicated that TNF-α-induced CXCL10, which affects the migration of osteocyte-derived osteoclast precursors, may enhance TNF-α-triggered osteoclast formation and bone resorption in vivo. [ABSTRACT FROM AUTHOR]

As of 2023, there were 39.9 million people living with Human Immunodeficiency Virus type 1 (HIV-1). Although great strides have been made in treatment options for HIV-1, and our understanding of the HIV-1 life cycle has vastly improved since the start of this global health crisis, a functional cure remains elusive. One of the main barriers to a cure is latency, which allows the virus to persist despite combined antiretroviral therapy (cART). Recently, we have found that exosomes, which are small, membrane-enclosed particles released by virtually all cell types and known to mediate intercellular communication, caused an increase in RNA Polymerase II loading onto the HIV-1 promoter. This resulted in the production of both short- and long-length viral transcripts in infected cells under cART. This current study examines the effects of exosome-associated kinases on bystander cells. The phospho-kinase profiling of exosomes revealed differences in the kinase payload of exosomes derived from uninfected and HIV-1-infected cells, with CDK10, GSK3β, and MAPK8 having the largest concentration differences. These kinases were shown to be biologically active and capable of phosphorylating substrates, and they modulated changes in the cell cycle dynamics of exposed cells. Given the relevance of such effects for the immune response, our results implicate exosome-associated kinases as new possible key contributors to HIV-1 pathogenesis that affect bystander cells. These findings may guide new therapeutic avenues to improve the current antiretroviral treatment regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last decade, buffalo farming has been attracting the interest of the research communities because of its high resilience in the current climate change context. Over their lifetime, animals face a range of infectious and non-infectious stressors on which successful recovery of their optimal performance may depend on different psychological conditions. Enabling both innate and adaptive immune responses, through the secretion of pro- and anti-inflammatory cytokines, plays a key role in the onset or progression of disease. This review describes the complex immune competence of the buffalo in the presence of the most prevalent infectious stressors, including mastitis, endometritis, and non-infectious stressors such as climate change-induced heat stress. Immune competence is a critical aspect of protecting animals from the negative consequences of disease. The activation of the immune response from inflammation is part of adaptive homeostasis that serves to eliminate danger, induce tissue repair, and restore tissue homeostasis. Therefore, the main goal for the organism is to control both the induction and suppression of inflammation and resist the onset of disease. In this condition, modulators of inflammatory responses are produced, including small proteins called cytokines, which exert a pro- or anti-inflammatory action in a context-dependent manner. Indeed, the cytokine profile could be considered a useful biomarker to determine the pathophysiology of certain diseases, such as mastitis, endometritis, change-induced heat stress, and zoonoses. Recently, buffalo breeding has attracted the interest of the research communities due to their high resilience; however, little is known about the immune mechanism activated under specific stressors. This review describes the complex immune competence of the buffalo in the presence of the most common infectious and non-infectious stressors. In addition, a brief description of methods for early diagnosis of disease using cytokine quantification will be introduced. [ABSTRACT FROM AUTHOR]

Background: Acute respiratory distress syndrome (ARDS) is causatively associated with excessive alveolar inflammation involving deregulated pro-inflammatory macrophage polarization. High-density lipoprotein (HDL) showed critical anti-inflammatory roles by modulating macrophage function, and its adverse transition to pro-inflammation has an important role in the pathogenesis of ARDS. However, the relationship between HDL protein constituents and functional remodeling is unknown in ARDS. Methods: Proteomic techniques were applied to examine the protein profile changes in HDL from septic-ARDS patients versus HDL from healthy controls across two distinct cohorts: a discovery cohort (8 patients and 8 healthy controls) and a validation cohort (22 patients and 10 healthy controls). The changed components significantly associated with prognosis were identified. Luminex assessed the levels of 38 plasma cytokines and chemokines. The in vitro constructed pro-SFTPB enriched HDL was applied to confirm the effect on M1 polarization of THP1-derived macrophage. Results: 18 proteins were validated from 102 changed HDL proteins identified in the discovery cohort, including HDL particle components, such as apolipoproteins, pro-inflammatory substances known as serum amyloid As (SAAs), and anti-oxidative proteins like paraoxonases (PONs). Among these proteins, only the increase of pro-SFTPB in HDL was significantly associated with poor prognosis of ARDS patients. Notably, HDL-pro-SFTPB level was correlated with plasma pro-inflammatory cytokines and chemokines levels. The correlation assay of pro-SFTPB with other HDL components showed that it was positively and negatively correlated with SAA2 and PON3, respectively. Furthermore, the in vitro studies confirmed that the pro-SFTPB enriched HDL significantly promoted M1 polarization of monocyte-derived macrophages. Conclusions: The increase of HDL-pro-SFTPB promotes HDL pro-inflammatory transition during septic ARDS, leading to exacerbated progression of ARDS through enhancing M1 macrophage polarization. HDL-pro-SFTPB could be a useful prognostic biomarker for septic ARDS. [ABSTRACT FROM AUTHOR]

We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors.Anti-PD1 monotherapy shows limited efficacy against HER2+ tumors. Here, the authors show that murine CAR macrophages (CAR-M) induce tumor microenvironment remodeling, T-cell mediated immunity and synergy with PD1 blockade, improving survival in immunocompetent female-mouse models of HER2+ solid tumors. [ABSTRACT FROM AUTHOR]

Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of the Atypical Chemokine Receptor 1 (ACKR1) acting as scavenger for multiple chemokines and the role of tumor necrosis factor receptor-associated factor 1 (TRAFD1) in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR using 2 independent proteomics datasets paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohn's disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies. The study uses GWAS for 40 circulating cytokines in meta-analyses of 74,783 individuals. With Mendelian randomization, key cytokines like G-CSF/CSF-3 and CXCL9/MIG are identified as potential causal mediators of asthma and Crohn's disease, respectively. [ABSTRACT FROM AUTHOR]

In the development of inflammatory bowel disease (IBD), peritoneal macrophages contribute to the resident intestinal macrophage pool. Previous studies have demonstrated that oral administration of L-fucose exerts an immunomodulatory effect and repolarizes the peritoneal macrophages in vivo in mice. In this study, we analyzed the phenotype and metabolic profile of the peritoneal macrophages from Muc2−/− mice, as well as the effect of L-fucose on the metabolic and morphological characteristics of these macrophages in vitro. The investigation utilized flow cytometry, quantitative PCR (qPCR), measurement of the intracellular ATP and Ca2+ concentrations, an analysis of mitochondrial respiration and membrane potential, and transmission electron microscopy (TEM) for ultrastructural evaluations. The Muc2−/− mice exhibited lower intracellular ATP and Ca2+ levels in their peritoneal macrophages, a higher percentage of stellate macrophages, and an increased oxygen consumption rate (OCR), combined with a higher percentage of mitochondria displaying an abnormal ultrastructure. Additionally, there was a five-fold increase in condensed mitochondria compared to their level in C57BL/6 mice. The number of CD209+ peritoneal macrophages was reduced three-fold, while the number of M1-like cells increased two-fold in the Muc2−/− mice. L-fucose treatment enhanced ATP production and reduced the expression of the Parp1, Mt-Nd2, and Mt-Nd6 genes, which may suggest a reduction in pro-inflammatory factor production and a shift in the differentiation of peritoneal macrophages towards the M2 phenotype. [ABSTRACT FROM AUTHOR]

Rosai-Dorfman disease (RDD) is a self-limited, idiopathic, non-neoplastic disorder characterized by the proliferation of phagocytic histiocytes, which can mimic malignant lymphoproliferative disease. Cases of RDD most commonly present as bilateral painless cervical lymphadenopathy, with lesser involvement of the axilla, inguinal, and mediastinal lymph nodes. We present the case of a 62-year-old woman with a history of endometrial serous carcinoma who underwent evaluation at a dedicated breast imaging department after positron emission tomography/computed tomography (PET/CT) revealed breast masses and axillary nodes with increased uptake of fluorodeoxyglucose (FDG). Upon clinical examination, she had bilateral palpable lumps in both breasts and axillae. Subsequent dedicated breast imaging with bilateral diagnostic mammography with tomosynthesis and bilateral complete breast ultrasound were suspicious for malignancy detecting bilateral breast masses and axillary lymphadenopathy corresponding to the FDG-avid findings on PET/CT. Ultrasound-guided core needle biopsies, however, revealed a diagnosis of RDD. This case highlights the unique characteristics of RDD with an atypical clinical presentation suspicious for breast cancer both clinically and radiologically. Keywords:Endometrial carcinoma, primary breast cancer, axillary lymphadenopathy, mammogram, core needle biopsy: [ABSTRACT FROM AUTHOR]

Hepatitis is a chronic inflammatory liver disease and an important cause of liver fibrosis, which can progress to cirrhosis and even hepatocellular carcinoma if left untreated. However, liver fibrosis is a reversible disease, so finding new intervention targets and molecular markers is the key to preventing and treating liver fibrosis. Ginseng, the roots of Panax ginseng C. A. Meyer, is a precious Traditional Chinese Medicines with high medicinal value and is known as the "king of all herbs", and its active ingredient, ginsenoside Rg3 is a rare saponin and a new class of drug, one of the most thoroughly and extensively studied in a large number of studies. Ginsenoside Rg3 is an active ingredient extracted from ginseng that possesses a variety of biological activities, including anti-inflammatory, antioxidant, and anti-fibrotic effects. Several studies have suggested that ginsenoside Rg3 may help reduce hepatic inflammation and oxidative stress, thereby slowing the progression of liver fibrosis. Ginsenoside Rg3 may have some therapeutic effects on liver fibrosis, and the underlying molecular mechanisms behind these effects are attributed to cellular autophagy, apoptosis, and anti-inflammation, as well as the modulation of antioxidant activity and multiple signaling pathways. The molecular mechanisms behind the inhibitory effect of ginsenoside Rg3 on hepatic fibrosis are reviewed, with a view to providing reference for related studies., Competing Interests: Declarations. Conflicts of interest: The authors declare no conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To explore biomarkers for the efficacy of lymphocyte immunotherapy (LIT) treating women with unexplained recurrent spontaneous abortion (URSA). Methods: Serum samples from 24 URSA potients who received LIT were collected at Peking University Third Hospital from December 2014 to June 2015. Semiquantitative sandwich-based antibody arrays containing 40 cytokines were used to screen target immune cytokines in the peripheral blood of URSA patients before and after LIT. Multifactor quantitative microsphere flow cytometry detection validated the levels of target cytokines. Based on the final pregnancy outcome after LIT, 24 URSA patients were divided into the full-term delivery group (15 cases) and the abortion group (9 cases). Furthermore, linear regression analysis were applied to evaluate the relationship between target cytokines and pregnancy outcomes. Results: Semiquantitative sandwich-based antibody arrays suggested that, among all 24 URSA patients included in this study, the intensities of the fluorescence signal were significantly lower post-LIT versus pre-LIT for the following cytokines: interleukin-15 (IL-15), monokine induced by γ-interferon (MIG), C-C motif chemokine ligand (CCL) 1 (all P <0.05). In the full-term delivery group, the intensities of the fluorescence signal post-LIT were significantly lower than pre-LIT for the following cytokines: IL-15, CCL1, macrophage inflammatory protein (MIP) 1α (all P <0.05). In the abortion group, the intensities of the fluorescence signal post-LIT were significantly lower than pre-LIT for the following cytokines: MIG, MIP-1δ (all P <0.05). Linear regression analysis showed that the intensity of the fluorescence signal of CCL11 was increased and the intensity of the fluorescence signal of soluble tumor necrosis factor receptor 2 (sTNFR2) was decreased in the full-term delivery group after LIT, the differences were statistically significant ( P =0.012, 0.029). Validation results of multifactor quantitative microsphere flow cytometry detection showed that the level of CCL11 was significantly increased ( P =0.001) and the level of sTNFR2 was significantly decreased ( P =0.001) in the full-term delivery group after LIT. Conclusion: CCL11 and sTNFR2 maybe serve as potential biomarkers that could predict pregnancy outcomes after LIT in women with URSA.