| First Author | Wang R | Year | 2021 |
| Journal | Nat Commun | Volume | 12 |
| Issue | 1 | Pages | 76 |
| PubMed ID | 33397953 | Mgi Jnum | J:300941 |
| Mgi Id | MGI:6504658 | Doi | 10.1038/s41467-020-20385-9 |
| Citation | Wang R, et al. (2021) Genetic and pharmacological inhibition of the nuclear receptor RORalpha regulates TH17 driven inflammatory disorders. Nat Commun 12(1):76 |
| abstractText | Full development of IL-17 producing CD4(+) T helper cells (TH17 cells) requires the transcriptional activity of both orphan nuclear receptors RORalpha and RORgammat. However, RORalpha is considered functionally redundant to RORgammat; therefore, the function and therapeutic value of RORalpha in TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORalpha is required for TH17 cell pathogenicity. T-cell-specific deletion of RORalpha reduces the development of experimental autoimmune encephalomyelitis (EAE) and colitis. Reduced inflammation is associated with decreased TH17 cell development, lower expression of tissue-homing chemokine receptors and integrins, and increased frequencies of Foxp3(+) T regulatory cells. Importantly, inhibition of RORalpha 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 RORalpha antagonist effectively inhibits human TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORalpha functions independent of RORgammat in programming TH17 pathogenicity and identifies RORalpha as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity. |
