Gut-derived metabolites drive Th17 cell pathogenicity in Multiple Sclerosis
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PROVIDER: PRJNA1188120 | ENA |
REPOSITORIES: ENA
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Project description:The gut-brain axis is an emerging factor in promoting multiple sclerosis (MS). However, the underlying mechanisms and strategies to target this axis are not established. Here, we investigated how the gut environment influences myelin-specific Th17 cell pathogenicity. We used the adoptive Th17 cell transfer experimental autoimmune encephalomyelitis (EAE) model and antibiotic treatment to modulate the intestinal microbiome. We observed a reduced pathogenic Th17 cell signature in the colon of antibiotics-treated mice. Treatment with fecal filtrates enhanced myelin-specific Th17 cell encephalitogenic properties both in vitro and in vivo. Feces metabolomic profiling identified altered tryptophan-derived metabolites, including indole-3-carboxylate (I3CA). Oral I3CA supplementation accelerated EAE development and I3CA concentration in blood samples from persons with MS (PwMS) was associated with increased disease severity mirrored by increased serum neurofilament light chain levels. Altogether, our study shows that microbiota-derived metabolites play a key role in the intestine during neuroinflammation, offering potential therapeutic insights for PwMS.
2025-07-15 | GSE282316 | GEO
Project description:In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and non-pathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis (EAE), an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase (ALK)4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances anti-inflammatory gene modules. Whole genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A-induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other anti-inflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1 and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a novel critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation.
2020-03-06 | GSE146439 | GEO
Project description:T helper cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here we demonstrate that high NaCl conditions induced a stable, pathogen-specific, anti-inflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and interleukin (IL)-17-expression in high-NaCl conditions. The NaCl-induced acquisition of an anti-inflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a pro-inflammatory and TGF--low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.
2020-04-15 | GSE148669 | GEO
Project description:Dysregulated Th17 cell responses underlie multiple inflammatory and autoimmune diseases, including autoimmune uveitis and its animal model, EAU. However, clinical trials targeting IL-17A in uveitis were not successful. Here, we found that Th17 cells were regulated by their own signature cytokine, IL-17A. Loss of IL-17A in autopathogenic Th17 cells did not reduce their pathogenicity and instead elevated their expression of the Th17 cell cytokines GM-CSF and IL-17F. Mechanistic in vitro studies revealed a Th17 cell-intrinsic autocrine loop triggered by binding of IL-17A to its receptor, leading to activation of transcription factor NFκB and induction of IL 24, which repressed the Th17 cytokine program. In vivo, IL-24 treatment ameliorated Th17-induced EAU, whereas silencing of IL-24 in Th17 cells enhanced disease. This regulatory pathway also operated in human Th17 cells. Thus, IL-17A limits pathogenicity of Th17 cells by inducing IL-24. These findings may explain the disappointing therapeutic effect in targeting IL-17A in uveitis.
2020-07-22 | GSE152534 | GEO
Project description:G-protein coupled receptors (GPCRs) are pivotal in regulating T cell responses in steady state and inflammation. GPCR expression was intensively studied in bulk cDNA of T cell populations, but limited data are available with respect to expression in individual cells. We here present an analysis of a selected set of 125 different GPCRs expressed on distinct single T cells under naive conditions and during experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. We found that neuroinflammation induces characteristic changes in GPCR heterogeneity and patterning, and we identified functionally relevant subgroups with specific GPCR expression profiles among spinal cord-infiltrating CD4 T cells. In spinal cord-infiltrating T helper 17 (Th17) cells, for example, expression of receptors such as Cxcr3, Cxcr4, P2ry10, or S1pr1 was associated with reduced pathogenicity, and we show that these correlations also exists on the protein level. Using CXCR4 and S1P1 as examples, we demonstrate that pharmacological targeting of these receptors is able to modulate Th17 pathogenicity in vitro and in vivo. Taken together, GPCR single-cell expression analysis provides a basis for the development of new strategies for pharmacological modulation of pathogenic immune cell subtypes.
2017-07-15 | GSE99778 | GEO
Project description:We report transcriptional profiling of mouse Th17 cells activated and expanded in vitro in the presence of Th17-inhibitory bacterial metabolites 3-oxoLCA and isoLCA.
2022-12-01 | GSE161977 | GEO
Project description:We report transcriptional profiling of mouse Th17 cells activated and expanded in vitro in the presence of Th17-inhibitory bacterial metabolites 3-oxoLCA and isoLCA.
2021-12-10 | GSE179740 | GEO
Project description:Cholinergic control of Th17 cell pathogenicity in experimental autoimmune encephalomyelitis
| PRJNA890323 | ENA
Project description:CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host’s ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.
2023-06-28 | GSE224960 | GEO
Project description:CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host’s ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.
2023-06-28 | GSE226795 | GEO