SOX-5 activates a novel RORγt enhancer to facilitate experimental autoimmune encephalomyelitis by promoting Th17 cell differentiation

AbstractT helper type 17 (Th17) cells have important functions in the pathogenesis of inflammatory and autoimmune diseases. Retinoid-related orphan receptor-γt (RORγt) is necessary for Th17 cell differentiation and functions. However, the transcriptional regulation of RORγt expression, especially at the enhancer level, is still poorly understood. Here we identify a novel enhancer of RORγt gene in Th17 cells, RORCE2. RORCE2 deficiency suppresses RORγt expression and Th17 differentiation, leading to reduced severity of experimental autoimmune encephalomyelitis. Mechanistically, RORCE2 is looped to RORγt promoter through SRY-box transcription factor 5 (SOX-5) in Th17 cells, and the loss of SOX-5 binding site in RORCE abolishes RORCE2 function and affects the binding of signal transducer and activator of transcription 3 (STAT3) to the RORγt locus. Taken together, our data highlight a molecular mechanism for the regulation of Th17 differentiation and functions, which may represent a new intervening clue for Th17-related diseases.

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SKI Expression Suppresses Pathogenic Th17 Cell Response and Mitigates Experimental Autoimmune Encephalomyelitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.707899 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ping Li ◽

Zengli Guo ◽

Yisong Y. Wan

Keyword(s):

Cell Differentiation ◽

Experimental Autoimmune Encephalomyelitis ◽

Th17 Cell ◽

Th17 Cells ◽

Transforming Growth Factor ◽

Ectopic Expression ◽

Transfer Model ◽

Autoimmune Encephalomyelitis ◽

Th17 Cell Differentiation ◽

Experimental Autoimmune

Pathogenic Th17 cells are critically involved in many autoimmune diseases, while non-pathogenic Th17 cells are more immune regulatory. Understanding the mechanisms of the induction and maintenance of pathogenic Th17 cells will benefit the development of therapeutic treatments of related diseases. We have shown that the transforming growth factor-β (TGFβ) induced SKI degradation and dissociation from Smad4 complex is a prerequisite for TGFβ-induced Th17 cell differentiation. However, it is unclear whether and how SKI regulates pathogenic Th17 differentiation, which does not require TGFβ cytokine. Here we showed that SKI expression was downregulated during pathogenic Th17 cell differentiation and the ectopic expression of SKI abrogated the differentiation of pathogenic Th17 cells. Functionally, using a knock-in mouse model, we found ectopic SKI expression specifically in T cells prevented myelin oligodendrocyte glycoprotein peptide (MOG33–55) induced experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis. We further revealed that induced SKI expression in already differentiated pathogenic Th17 cells reduced the maintenance of Th17 program and ameliorated EAE in an adoptive T cell transfer model. Therefore, our study provides valuable insights of targeting SKI to modulate pathogenic Th17 cell function and treat Th17-related diseases.

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Eriodictyol suppresses Th17 differentiation and the pathogenesis of experimental autoimmune encephalomyelitis

Food & Function ◽

10.1039/c9fo03019k ◽

2020 ◽

Vol 11 (8) ◽

pp. 6875-6888

Author(s):

Ting Yang ◽

Xing Li ◽

Jie Yu ◽

Xin Deng ◽

Pei-Xin Shen ◽

...

Keyword(s):

Cell Differentiation ◽

Experimental Autoimmune Encephalomyelitis ◽

Th17 Cell ◽

Clinical Signs ◽

Citrus Fruits ◽

Autoimmune Encephalomyelitis ◽

Th17 Cell Differentiation ◽

Th17 Differentiation ◽

Experimental Autoimmune

Eriodictyol (EDT), a natural flavonoid abundant in citrus fruits and peanuts, alleviates clinical signs of EAE by suppressing RORγt-Regulated Th17 cell differentiation.

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