Retinoic Acid Receptor-Related Receptor Alpha Ameliorates Autoimmune Arthritis via Inhibiting of Th17 Cells and Osteoclastogenesis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis characterized by progressive joint destruction. IL-17-producing CD4(+) T (Th17) cells play pivotal roles in RA development and progression. Retinoic acid receptor-related orphan receptor alpha (ROR alpha) is a negative regulator of inflammatory responses, whereas ROR gamma t, another member of the ROR family, is a Th17 lineage-specific transcription factor. Here, we investigated the immunoregulatory potential of ROR alpha in collagen-induced arthritis (CIA) mice, an experimental model of RA. Cholesterol sulfate (CS) or SR1078, a ligand of ROR alpha, inhibited ROR gamma t expression and Th17 differentiation in vitro. In addition, fortification of ROR alpha in T cells inhibited the expression levels of glycolysis-associated genes. We found that ROR alpha overexpression in CIA mice attenuated the clinical and histological severities of inflammatory arthritis. The anti-arthritic effect of ROR alpha was associated with suppressed Th17 differentiation and attenuated mTOR-STAT3 signaling in T cells. Furthermore, altered ROR alpha activity could directly affect osteoclastogenesis implicated in progressive bone destruction in human RA. Our findings defined a critical role of ROR alpha in the pathogenesis of RA. These data suggest that ROR alpha may have novel therapeutic uses in the treatment of RA.