Genetic and pharmacological inhibition of the nuclear receptor RORα regulates TH17 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 ROR alpha and ROR gamma t. However, ROR alpha is considered functionally redundant to ROR gamma t; therefore, the function and therapeutic value of ROR alpha in T(H)17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of ROR alpha is required for T(H)17 cell pathogenicity. T-cell-specific deletion of ROR alpha 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 ROR alpha 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 ROR alpha antagonist effectively inhibits human T(H)17 cell differentiation and memory cytokine secretion. Together, these data suggest that ROR alpha functions independent of ROR gamma t in programming T(H)17 pathogenicity and identifies ROR alpha as a safer and more selective therapeutic target for the treatment of T(H)17-mediated autoimmunity. Unlike ROR alpha, which has been thought to be somewhat redundant, ROR gamma t has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that ROR alpha is important in Th17 differentiation and that ROR alpha deletion or a small molecule inhibitor of ROR alpha can reduce disease in EAE and colitis mouse models.

Automated summary

The study demonstrates the importance of ROR alpha in the pathogenicity of T(H)17 cells, and its deletion or inhibition with a small molecule antagonist can reduce disease development in EAE and colitis mouse models.