Pharmacologic Repression of Retinoic Acid Receptor-Related Orphan Nuclear Receptor γ Is Therapeutic in the Collagen-Induced Arthritis Experimental Model

Objective. The nuclear receptor retinoic acid receptor-related orphan nuclear receptor gamma (ROR gamma; T cell-specific isoform ROR gamma t) is a key regulator of Th17 cell differentiation, controlling the production of the inflammatory cytokine interleukin-17 (IL-17). Lipopolysaccharide (LPS) stimulation of monocytes leads to the induction of ROR gamma. We previously showed that the potent and selective inverse agonist of ROR gamma, SR2211, was effective at suppressing IL-17 production in EL4 cells. The aim of this study was to examine the effects of SR2211 treatment on proinflammatory cytokine expression in LPS-stimulated RAW 264.7 cells as well as on joint inflammation in vivo in mice with collagen-induced arthritis (CIA). Methods. Collagen was injected into the tail of DBA mice, followed by a booster inoculation 21 days later. Three days prior to the booster inoculation, SR2211 was administered twice daily for 15 days. Thymus, spleen, and draining lymph nodes (DLNs) were then harvested, and Th17 cell differentiation and DLN stimulation were performed. Results. Treatment of Th17 cells with SR2211 suppressed the expression and production of inflammatory cytokines. Likewise, SR2211 reduced inflammatory cytokine production in LPS-stimulated RAW 264.7 cells. Mice with CIA that received SR2211 twice daily for 15 days exhibited a statistically significant reduction in joint inflammation as compared to mice that received only vehicle. Interestingly, systemic Th1 cell activation was detected in SR2211-treated mice with CIA, as indicated by an increase in interferon-gamma levels. Conclusion. The findings of this study support the idea of targeting ROR gamma to therapeutically repress inflammatory T cell function and macrophage activation in humans with rheumatoid arthritis. Compounds such as SR2211 have potential utility for the treatment of inflammatory disease.