IL-6/STAT3 pathway induced deficiency of RFX1 contributes to Th17-dependent autoimmune diseases via epigenetic regulation.

Abstract

Epigenetic modifications affect the differentiation of T cell subsets and the pathogenesis of autoimmune diseases, but many mechanisms of epigenetic regulation of T cell differentiation are unclear. Here we show reduced expression of the transcription factor RFX1 in CD4+ T cells from patients with systemic lupus erythematosus, which leads to IL-17A overexpression through increased histone H3 acetylation and decreased DNA methylation and H3K9 tri-methylation. Conditional deletion of Rfx1 in mice exacerbates experimental autoimmune encephalomyelitis and pristane-induced lupus-like syndrome and increases induction of Th17 cells. In vitro, Rfx1 deficiency increases the differentiation of naive CD4+ T cells into Th17 cells, but this effect can be reversed by forced expression of Rfx1. Importantly, RFX1 functions downstream of STAT3 and phosphorylated STAT3 can inhibit RFX1 expression, highlighting a non-canonical pathway that regulates differentiation of Th17 cells. Collectively, our findings identify a unique role for RFX1 in Th17-related autoimmune diseases.

• Authors: Ming Zhao, Yixin Tan, Qiao Peng, Cancan Huang, Yu Guo, Gongping Liang, Bochen Zhu, Yi Huang, Aiyun Liu, Zijun Wang, Mengying Li, Xiaofei Gao, Ruifang Wu, Haijing Wu, Hai Long, Qianjin Lu
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 583 (02 08 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29422534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-6
• Regulatory Factor X1
• STAT3 Transcription Factor

Topics

• Adolescent
• Adult
• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• Cell Differentiation (genetics, immunology)
• Cells, Cultured
• Encephalomyelitis, Autoimmune, Experimental (genetics, immunology, metabolism)
• Epigenesis, Genetic
• Female
• HEK293 Cells
• Humans
• Interleukin-6 (pharmacology)
• Jurkat Cells
• Lupus Erythematosus, Systemic (genetics, immunology, metabolism)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Middle Aged
• Phosphorylation
• Regulatory Factor X1 (genetics, metabolism)
• STAT3 Transcription Factor (genetics, metabolism)
• Signal Transduction (genetics)
• Th17 Cells (drug effects, immunology, metabolism)
• Young Adult