Genetic and pharmacological inhibition of the nuclear receptor RORα regulates T(H)17 driven inflammatory disorders

Full development of IL-17 producing CD4(+) T helper cells (T(H)17 cells) requires the transcriptional activity of both orphan nuclear receptors RORα and RORγt. However, RORα is considered functionally redundant to RORγt; therefore, the function and therapeutic value of RORα in T(H)17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for T(H)17 cell pathogenicity. T-cell-specific deletion of RORα reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased T(H)17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3(+) T regulatory cells. Importantly, inhibition of RORα with a selective small molecule antagonist mostly phenocopies our genetic data, showing potent suppression of the in vivo development of both chronic/progressive and relapsing/remitting EAE, but with no effect on overall thymic cellularity. Furthermore, use of the RORα antagonist effectively inhibits human T(H)17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming T(H)17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of T(H)17-mediated autoimmunity.