1. Genetic and pharmacological inhibition of the nuclear receptor RORα regulates TH17 driven inflammatory disorders
- Author
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Amber Eliason, Laura A. Solt, Ran Wang, Sarah A. Mosure, Sean Campbell, Mohammed Amir, Theodore M. Kamenecka, Mark S. Sundrud, and Molly A. Bassette
- Subjects
0301 basic medicine ,Multidisciplinary ,Cellular differentiation ,Science ,Experimental autoimmune encephalomyelitis ,General Physics and Astronomy ,FOXP3 ,General Chemistry ,Biology ,medicine.disease ,Acquired immune system ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,03 medical and health sciences ,Chemokine receptor ,030104 developmental biology ,0302 clinical medicine ,Nuclear receptor ,RAR-related orphan receptor gamma ,medicine ,Cytokine secretion ,030215 immunology - Abstract
Full development of IL-17 producing CD4+ T helper cells (TH17 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 TH17 cells is unclear. Here, using mouse models of autoimmune and chronic inflammation, we show that expression of RORα is required for TH17 cell pathogenicity. T-cell-specific deletion of RORα 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 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 TH17 cell differentiation and memory cytokine secretion. Together, these data suggest that RORα functions independent of RORγt in programming TH17 pathogenicity and identifies RORα as a safer and more selective therapeutic target for the treatment of TH17-mediated autoimmunity. Unlike RORα, which has been thought to be somewhat redundant, RORγt has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that RORα is important in Th17 differentiation and that RORα deletion or a small molecule inhibitor of RORα can reduce disease in EAE and colitis mouse models.
- Published
- 2021