Tetramerization of Transcription Factor STAT5 in Monocytes Promotes Autoimmune-mediated Neuroinflammation via the Regulation of CCL17
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PROVIDER: PRJNA753868 | ENA |
REPOSITORIES: ENA
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Project description:STAT5 plays a critical role in mediating cellular responses following cytokine stimulation. The activated STAT5 proteins can form dimers and tetramers with distinct biological functions. The role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knock-in (DKI) mouse strain, we report here that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE). The mild EAE phenotype observed in DKI mice correlates with the impaired extravasation of pathogenic Th17 cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrated that STAT5 tetramerization regulates the GM-CSF-dependent production of CCL17 by MDCs. Importantly, DKI Th17 cells expanded with CCL17 exhibit more severe EAE. Mechanistically, the effect of CCL17 is dependent on the activity of the integrin VLA-4. Thus, our study uncovered a novel GM-CSF-STAT5 tetramer-CCL17 pathway that promotes autoimmune neuroinflammation via the regulation of Th17 cell migration.
2021-11-30 | GSE181924 | GEO
Project description:Oligodendrocyte regulation during autoimmune neuroinflammation
| PRJNA755962 | ENA
Project description:In response to external stimuli during immune responses, monocytes can have multifaceted roles such as pathogen clearance and tissue repair. However, aberrant control of monocyte activation can result in chronic inflammation and subsequent tissue damage. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces monocyte differentiation into a heterogenous population of monocyte-derived dendritic cells (moDCs) and macrophages. However, the downstream molecular signals that dictate the differentiation of monocytes under pathological conditions is incompletely understood. We report here that the GM-CSF-induced STAT5 tetramerization is a critical determinate of monocyte fate and function. Monocytes require STAT5 tetramers to differentiate into moDCs, whereas STAT5 tetramer deficiency yields a macrophage phenotype. In the dextran sulfate sodium model of colitis, STAT5 tetramer-deficient monocytes exacerbate disease severity. Mechanistically, GM-CSF signaling in STAT5 tetramer-deficient monocytes results in the overexpression arginase I and a reduction in nitric oxide synthesis following stimulation with lipopolysaccharide. Correspondingly, the inhibition of arginase I activity and supplementation with a sustained concentration of nitric oxide ameliorates the worsened colitis in STAT5 tetramer-deficient mice. Thus, this study suggests a protective role of STAT5 tetramers in inflammatory bowel disease through the regulation of arginine metabolism. We previously reported that STAT5 tetramerization in monocytes is detrimental in autoimmune-mediated neuroinflammation. This study highlights the opposing role of STAT5 tetramers in inflammatory bowel disease.
2023-04-11 | GSE207676 | GEO
Project description:STAT5 functions in human inflammatory monocytes is largely unknown. We identified the anti-inflammatory function of CD127-STAT5 axis in human monocytes. To investigate the mechanism underlying STAT5-mediated anti-inflammatory regulation, thoroughly dissecting the STAT5 genomic distribution in human monocytes would be informative. Therefore, we performed anti-STAT5 ChIP-seq analyses for CD127high monocytes under LPS stimulation to globally characterize the STAT5 occupancy in CD127 expressing human monocytes.
2021-12-20 | GSE173490 | GEO
Project description:The present study had the purpose to analyze the transcriptional state of oligodendrocytes in an animal model of multiple scleroris resembling autoimmune neuroinflammation and compared with control mice treated with ovalbumin. The results revealed that oligodendrocytes from the EAE (experimental autoimmune encephalomyelitis) model upregulate genes that are involved in immune processes providing evidence that oligodendrocytes can develop an immune phenotype in particular neuroinflammatory conditions.
2021-08-21 | GSE182341 | GEO
Project description:Autoimmune diseases such as multiple sclerosis (MS) develop because of failed peripheral immune tolerance for a specific self-antigen (Ag). Numerous approaches for Ag-specific suppression of autoimmune neuroinflammation have been proven in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. One such approach is intravenous (i.v.) tolerance induction by injecting a myelin Ag used for EAE induction. However, the translation of this and similar experimental strategies into therapy for MS has been hampered by uncertainty regarding relevant myelin Ags in MS patients. To address this issue, we developed a therapeutic strategy that relies on oligodendrocyte (Ol)-derived extracellular vesicles (Ol-EVs), which naturally contain multiple myelin Ags. Ol-EVs injected i.v. suppressed disease in a myelin Ag-dependent manner, both prophylactically and therapeutically, in several EAE models. The treatment was safe and restored immune tolerance by inducing immunosuppressive monocytes and apoptosis of autoreactive encephalitogenic CD4+ T cells. Finally, we show that human Ols also release EVs containing most relevant myelin Ags, providing a basis for their use in MS therapy. These findings introduce an approach for suppressing central nervous system autoimmunity in a myelin Ag-specific manner.
2020-05-17 | MSV000085434 | MassIVE
Project description:Identifying a discriminating expression pattern of inflammatory genes in monocytes of patients with autoimmune diabetes
2008-08-01 | E-MEXP-1516 | biostudies-arrayexpress
Project description:Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue and the initial response of microglia determines the severity of neuroinflammatory diseases. CD83 has been associated with early activation of microglia in various disease settings albeit its functional relevance for microglial biology was still elusive. Thus, we conducted a thorough assessment of CD83 regulation in microglia as well as its impact on microglial mediated neuroinflammation. Here, we describe for the first time that CD83 expression in microglia is not only associated with cellular activation but also with pro-resolving functions. Conditional deletion of CD83 causes malfunctioning responses to myelin debris, which results in an over-activated state during autoimmune neuroinflammation. Subsequently, CD83-deficient microglia recruit more pathogenic immune cells to the central nervous system and deteriorate resolving mechanism, which exacerbates the disease. Thus, CD83 in microglia orchestrates cellular activation and consequently, also resolution of neuroinflammation.
2023-06-28 | GSE230753 | GEO
Project description:Human peripheral monocytes have been categorized into three subsets based on differential expression levels of CD14 and CD16. However, the factors that influence the distribution of monocyte subsets and the roles which each subset plays in autoimmunity are not well studied. To compare the gene expression profiling 1) on intermediate monocytes CD14++CD16+ monocytes between healthy donors and autoimmune uveitis patients and 2) among 3 monocyte subsets in health donors, here we purified circulating intermediate CD14++CD16+ monocytes from 5 patients with autoimmune uveitis (labeled as P1-5) and 4 healthy donors (labeled as HD1-4) by flow cytometry and isolated total RNA to proceed microarray assay. In addition, we also purified CD14+CD16++ (non-classical monocytes) and CD14++CD16- (classical monocytes) from 4 healthy donors to do microarray. We demonstrate that CD14++CD16+ monocytes from patients and healthy control donors share a similar gene expression profile. The CD14+CD16++ cells (non-classical monocytes) display the most distinctive gene expression profiling when compared to intermediate CD14++CD16+ monocytes and classical CD14++CD16- monocytes.
2015-03-17 | GSE66936 | GEO
Project description:A20 is a ubiquitin-modifying protein that negatively regulates canonical NF-κB signaling and mutations in A20/TNFAIP3 have been associated with a variety of autoimmune diseases, including multiple sclerosis (MS). We found that deletion of A20 in central nervous system (CNS) endothelial cells (BEC) enhances experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. These mice showed increased numbers of CNS-infiltrating immune cells during neuroinflammation and in the steady state. While the integrity of the barrier was not impaired, we observed a strong activation of the endothelium in A20ΔBEC mice, with dramatically increased levels of the adhesion molecules ICAM-1 and VCAM-1. We furthermore discovered ICOSL as novel adhesion molecule expressed by A20-deficient BECs. Silencing of ICOSL in BECs ameliorated the severity of an active EAE disease in wildtype mice and significantly delayed the onset of symptom development. Furthermore, blocking of ICOSL on primary CNS-derived endothelial cells impaired the adhesion of different T cell populations to the monolayer. Taken together, we here report a novel function of A20-regulated ICOSL expressed on CNS endothelial cells during inflammation. We propose that BEC-ICOSL contributes to the firm adhesion of T cells to the barrier, promoting T cell transmigration into the CNS and eventually driving autoimmune neuroinflammation.
2023-11-03 | GSE221318 | GEO