Small molecules targeting RORγt inhibit autoimmune disease by suppressing Th17 cell differentiation

Abstract

Th17 cells, a lymphocyte subpopulation that is characterized by the expression of the transcription factor "retinoic acid receptor-related orphan receptor gamma-t" (RORγt), plays an important role in the pathogenesis of autoimmune disease. The current study was set up to discover novel and non-steroidal small-molecule inverse agonists of RORγt and to determine their effects on autoimmune disease. Structure-based virtual screening (SBVS) was used to find compounds targeting RORγt. Flow cytometry was used to detect the Th17 cell differentiation. Inverse agonists were intraperitoneally administered to mice undergoing experimental autoimmune uveitis (EAU), experimental autoimmune encephalomyelitis (EAE) or type 1 diabetes. The effects of the inverse agonists were evaluated by clinical or histopathological scoring. Among 1.3 million compounds screened, CQMU151 and CQMU152 were found to inhibit Th17 cell differentiation without affecting the differentiation of Th1 and Treg lineages (both P = 0.001). These compounds also reduced the severity of EAU (P = 0.01 and 0.013) and functional studies showed that they reduced the number of Th17 cell and the expression of IL-17(Th17), but not IFN-γ(Th1) and TGF-β(Treg) in mouse retinas. Further studies showed that these compounds may reduce the expression of p-STAT3 by reducing the positive feedback loop of IL-17/IL-6/STAT3. These compounds also reduced the impaired blood-retinal barrier function by upregulating the expression of tight junction proteins. These compounds were also found to reduce the severity of EAE and type 1 diabetes. Our results showed that RORγt inverse agonists may inhibit the development of autoimmune diseases and may provide new clues for the treatment of Th17-mediated immune diseases.

Role of Interleukin-17 in Acute Pancreatitis

“…Several RORγt antagonists are used in ongoing clinical trials, such as GSK805 and TAK-828F, which both have shown prospective efficacy in preclinical models and animal models of inflammatory diseases ( 125 , 126 ). However, several questions remain about RORγt antagonism, including potential mechanisms of action, key target cells and effects on the homeostatic balance within Th17 cells and Treg cells ( 127 ). Furthermore, miR-155 is closely related to the differentiation of CD4 + T cells to Th17 cells.…”

Qing Zao Fang (QZF) Alleviates the Inflammatory Microenvironment of the Submandibular Gland in Sjögren’s Syndrome Based on the PI3K/Akt/HIF-1α/VEGF Signaling Pathway

“…IL-17A is a powerful proinflammatory factor that can be vastly secreted by Th17 cells; moreover, IL-17A also can act on a variety of cell types for the inducing expression of cytokines including proinflammatory cytokines, chemokines, and matrix metalloproteinases [ 11 , 12 ]. Similar to Th1 and Th2 cell subgroups, the steroid receptor type nuclear receptor ROR γ t also is the corresponding major regulators of Th17 cells [ 13 ]. Studies have shown that ROR γ t can promote the expression of IL-17A and IL-17F by naive T cells and therefore regulate the secretion of IL-17 [ 14 ], while regulatory T (Treg) cells which can inhibit immune response play an important role in immune balance maintaining and regulating immunity [ 15 ].…”

Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats

“…These findings are surprising considering previous studies of RORC inhibition in a variety of inflammatory models including antigen-induced arthritis ( 17 ), imiquimod-induced psoriasis ( 21 ), IL-23 induced skin inflammation ( 30 ), intestinal inflammation ( 22 , 31 ). Recently, Tan et al ( 24 ) showed the reduced clinical severity of experimental autoimmune uveitis (EAU), and EAE using two different RORc antagonists (CQMU151 and CQMU152) ( 24 ).…”

“…Genetic lack of RORγt protected mice against experimental autoimmune encephalomyelitis (EAE), induced defects in Th17 differentiation and prevented T-cell-transfer-mediated colitis ( 8 , 20 ). Pre-clinical studies in animal models, including imiquimod-induced psoriasis ( 21 ), spontaneous colonic inflammation ( 22 ), antigen induced arthritis ( 17 ), EAE ( 23 ), and experimental autoimmune uveitis (EAU) ( 24 ), confirmed that RORC inhibition markedly reduces local and systemic IL-17A levels and decreases tissue inflammation. Moreover, expression of IL-17F and IL-22 was also reduced upon in vivo RORC inhibition ( 21 , 23 ).…”