GSK-805

Retinal and choroidal neovascularization (RNV and CNV) are critical pathological features of vision-threatening ocular disorders. This study investigated the role of retinoic acid receptor-related orphan receptor γt (RORγt) in the regulation of RNV and CNV formation using oxygen-induced retinopathy (OIR) and CNV mouse models, and explored its underlying mechanisms. We demonstrated that RORγt expression was significantly elevated in retinal tissues of both models, co-localizing with IL-23 receptor (IL-23R) and T-cell receptor γδ (TCRγδ), indicating its primary expression in Th17 and γδT cells. Pharmacological inhibition of RORγt with GSK805 effectively reduces pathological NV and leakage, as evidenced by decreased retinal NV areas, vaso-obliteration areas and Evans blue extravasations in the OIR model and reduced vascular leakage and CNV areas in the CNV model. Additionally, GSK805 treatment downregulated pro-inflammatory cytokines (IL-22 and IL-17A), angiogenic factors (angiopoietin 2, PDGF-B, and PDGFR-β), and inflammasome components (NLRP3 and ASC), while modulating macrophage polarization by reducing M1 markers and increasing M2 markers. These findings reveal that RORγt plays a supportive role in NV by influencing key inflammatory and angiogenic pathways, suggesting that RORγt inhibition may represent a promising therapeutic strategy for NV-related retinal diseases.

Liver fibrosis is a global health problem. IL-17A has proven profibrogenic properties in liver disease making it an interesting therapeutic target. IL-17A is regulated by RORγt and produced by Th17 CD4+ and γδ-T cells. We hypothesized that blocking IL-17A production will limit fibrosis progression by reducing recruitment of inflammatory cells. Herein, we tested the therapeutic potential of 2 novel RORγt inverse agonists (2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene) in a mouse model of CCl4-induced liver injury. C57BL/6 mice received 2 weekly injections of CCl4 for 4 weeks. As of week 3, mice were treated with the 2 novel inverse agonists (TF-S10 and TF-S14) and GSK805 as a positive control. Mice treated with the inverse agonists showed reduced immune cells infiltrate around the portal and central veins. TF-S14 significantly reduced AST levels (P < 0.05), and all inhibitors led to an improvement in relative liver weight (liver index). Flow cytometry analysis demonstrated that all inhibitors reduced the numbers of intrahepatic lymphocytes (CD4+, CD8+, and γδ-T cells, P < 0.05), and myeloid (CD11b+) cells (P = 0.04), most significantly eosinophils (P < 0.05). Furthermore, IL-17A production by CD4+ and γδ-T cells was diminished (P < 0.05 and P < 0. 01, respectively). Finally, livers from inhibitors-treated mice showed decreased markers of hepatic stellate cell activation (desmin and ɑ-smooth muscle actin [ɑ-SMA]) and significantly reduced expression of the profibrogenic genes (Col1a1, Acta, Loxl2, and Tgfβ) (P < 0.001). This was accompanied by diminished collagen deposition as measured by Picrosirius Red staining (P < 0.001). In conclusion, our results suggest that inhibition of the IL-17A pathway could be a promising therapeutic strategy for liver fibrosis.