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Proc Natl Acad Sci U S A. 2019 Sep 10;116(37):18528-18536. doi: 10.1073/pnas.1907563116. Epub 2019 Aug 27.

The nuclear receptor REV-ERBα modulates Th17 cell-mediated autoimmune disease.

Author information

1
NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037.
2
Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093.
3
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037.
4
Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458.
5
Medical Scientist Training Program, University of California San Diego, La Jolla, CA 92093.
6
Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO 63104.
7
Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu yzheng@salk.edu.
8
Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037.
9
NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu yzheng@salk.edu.

Abstract

T helper 17 (Th17) cells produce interleukin-17 (IL-17) cytokines and drive inflammatory responses in autoimmune diseases such as multiple sclerosis. The differentiation of Th17 cells is dependent on the retinoic acid receptor-related orphan nuclear receptor RORγt. Here, we identify REV-ERBα (encoded by Nr1d1), a member of the nuclear hormone receptor family, as a transcriptional repressor that antagonizes RORγt function in Th17 cells. REV-ERBα binds to ROR response elements (RORE) in Th17 cells and inhibits the expression of RORγt-dependent genes including Il17a and Il17f Furthermore, elevated REV-ERBα expression or treatment with a synthetic REV-ERB agonist significantly delays the onset and impedes the progression of experimental autoimmune encephalomyelitis (EAE). These results suggest that modulating REV-ERBα activity may be used to manipulate Th17 cells in autoimmune diseases.

KEYWORDS:

autoimmunity; nuclear receptors; transcriptional repressor

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