Genetic and pharmacological inhibition of the nuclear receptor RORα regulates TH17 driven inflammatory disorders

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.

RORα is critical for mTORC1 activity in T cell-mediated colitis

“…Teichmann et al reported that RORa is restrictedly expressed in activated T cells and promotes lung inflammation during N. brasiliensis infection (Haim-Vilmovsky et al, 2019). In our work, we found that RORa promotes T cell pathogenicity in gut inflammation, consistent with the founding of Wang et al (2021). Meanwhile, some targets were consistently regulated in different models such as Tnfrsf25 (Haim-Vilmovsky et al, 2019;Malhotra et al, 2018) (Figure 4A).…”

Transcriptional Interactomic Inhibition of RORα Suppresses Th17-Related Inflammation

“…The Efficiency and Kinetics of the Intra-Nuclear Delivery of nt-RORα-TMD RORα is known as a transcription factor essential for the development and functions of Th17 cells. 20 However, RORα is also considered functionally redundant to RORγt. To investigate the functions of RORα in vitro and in vivo under normal physiological condition without genetic alteration such as gene knockout, knock-down, or overexpression of RORα, nt-RORα-TMD was generated by fusing Hph-1-PTD with RORα-TMD composed of DBD and hinge region of RORα (Figure 1A).…”

“…It has been known that RORα binds to the promoter region and induces the expression of the IL-17A gene. 14 , 20 To confirm the inhibitory function of nt-RORα-TMD on RORα-mediated IL-17A expression, wild-type RORα-expressing vector and IL-17A promoter-luciferase vector were co-transfected into HEK293 cells. Then, the transfected cells were incubated with either nt-RORα-TMD or nt-RORα-TMD (R42A/R43G).…”

“…These results are consistent with the previous report that the function of RORα is independent of RORγt in developing the pathogenicity of Th17 cells. 20 In several studies, smallmolecule inhibitors or siRNA have been used to https://doi.org/10.2147/JIR.S344031…”

“… 27 , 28 In Th17 cells, which are significantly implicated in various inflammatory disorders, RORα has been reported as a transcription factor for Th17 differentiation and the expression of Th17-related genes, including its cytokines. 14 , 20 , 29 , 30 Although the function of RORα has been revealed in Th17 cells, the studies on regulating the function of Th17 cells targeting RORα under the normal physiological condition without using genetic alteration have not been sufficiently reported.…”