Genetic and pharmacological inhibition of the nuclear receptor RORα regulates T_H17 driven inflammatory disorders.

Abstract

Full development of IL-17 producing CD4⁺ T helper cells (T_H17 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_H17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for T_H17 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_H17 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_H17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming T_H17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of T_H17-mediated autoimmunity.