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 (RORα) is a negative regulator of inflammatory responses, whereas RORγt, another member of the ROR family, is a Th17 lineage-specific transcription factor. Here, we investigated the immunoregulatory potential of RORα in collagen-induced arthritis (CIA) mice, an experimental model of RA. Cholesterol sulfate (CS) or SR1078, a ligand of RORα, inhibited RORγt expression and Th17 differentiation in vitro. In addition, fortification of RORα in T cells inhibited the expression levels of glycolysis-associated genes. We found that RORα overexpression in CIA mice attenuated the clinical and histological severities of inflammatory arthritis. The anti-arthritic effect of RORα was associated with suppressed Th17 differentiation and attenuated mTOR-STAT3 signaling in T cells. Furthermore, altered RORα activity could directly affect osteoclastogenesis implicated in progressive bone destruction in human RA. Our findings defined a critical role of RORα in the pathogenesis of RA. These data suggest that RORα may have novel therapeutic uses in the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a progressive autoimmune polyarthritis characterized by hyperplastic synovial membrane and subsequent structural damage in affected joints
To determine whether RORα overexpression could regulate the development of Th17 cells, murine T cells were cultured in the presence of Cholesterol sulfate (CS), a putative natural ligand of RORα [29]
Overexpression of RORα by CS resulted in significantly (P < 0.05) attenuated IL-17 expression in LBRM-33 cells, whereas Foxp3 expression was reciprocally and significantly (P < 0.05) increased (Figures 1E,F). These results suggest that inducing RORα activity in T cells may represent a novel treatment strategy for management of various Th17-associated diseases, including RA
Summary
Rheumatoid arthritis (RA) is a progressive autoimmune polyarthritis characterized by hyperplastic synovial membrane and subsequent structural damage in affected joints. It leads to significant deterioration of the quality of life of RA patients. The pathogenesis of RA is not fully understood, CD4+ T cells have been shown to play critical roles in the development and progression of RA. There is accumulating evidence that the percentage of circulating Treg cells in patients with active RA is reduced compared to that in healthy controls or those with inactive RA [10]. The reciprocal regulation of Th17/Treg imbalance can be targeted to satisfy the unmet needs for treatmentresistant RA patients, including patients who are currently using biologics, namely, genetically engineered proteins derived from human genes
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