Tiam1/Rac1 complex controls Il17a transcription and autoimmunity
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Nature Publishing Group
Abstract
RORγt is a master transcription factor of Th17 cells and considered as a promising drug target for the treatment of autoimmune diseases. Here, we show the guanine nucleotide exchange factor, Tiam1, and its cognate Rho-family G protein, Rac1, regulate interleukin (IL)17A transcription and autoimmunity. Whereas Tiam1 genetic deficiency weakens IL-17A expression partially and inhibits the development of experimental autoimmune encephalomyelitis (EAE), deletion of Rac1 in T cells exhibits more robust effects on Th17 cells and EAE. We demonstrate Tiam1 and Rac1 form a complex with RORγt in the nuclear compartment of Th17 cells, and together bind and activate the Il17 promoter. The clinical relevance of these findings is emphasized by pharmacological targeting of Rac1 that suppresses both murine and human Th17 cells as well as EAE. Thus, our findings highlight a regulatory pathway of Tiam1/Rac1 in Th17 cells and suggest that it may be a therapeutic target in multiple sclerosis.
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Animals, Autoimmunity, Encephalomyelitis, autoimmune, experimental, Female, Humans, Interleukin-17, Mice, inbred c57bl, Mice, knockout, Nuclear receptor subfamily 1, group f, member 3, Promoter regions, genetic, Protein binding, Rac1 gtp-binding protein, T-lymphoma invasion and metastasis-inducing protein 1, Th17 cells, Transcription, genetic, Murinae, 4 amino 6 [2 [[4 (diethylamino) 1 methylbutyl]amino] 6 methyl 4 pyrimidinyl] 2 methylquinoline, Cd4 antigen, Gamma interferon, Granulocyte macrophage colony stimulating factor, Guanine nucleotide exchange factor, Hermes antigen, Immunoglobulin g antibody, Interleukin 10, Interleukin 12, Interleukin 17, Interleukin 17f, Interleukin 21, Interleukin 22, Interleukin 23, Interleukin 23 receptor, Interleukin 6, Interleukin 9, L selectin, Myelin oligodendrocyte glycoprotein, Protein, Rac1 protein, Retinoid related orphan receptor gamma, Stat3 protein, Tiam1 protein, Transforming growth factor beta1, Unclassified drug, T lymphoma invasion and metastasis inducing protein 1, Cells and cell components, Drug, Gene expression, Genome, Immune response, Mutation, Animal experiment, Animal model, Article, Cell compartmentalization, Controlled study, Experimental autoimmune encephalomyelitis, Gene deletion, Gene targeting, Genetic analysis, Human, Human cell, Mouse, Nonhuman, Promoter region, Protein expression, T lymphocyte, Th17 cell, Transcription regulation, Animal, C57bl mouse, Deficiency, Genetic transcription, Genetics, Immunology, Knockout mouse, Metabolism, Pathology