Dabbaghizadeh Afrooz, Dion Jessica, Maali Yousef, Fouda Ahmed, Bédard Nathalie, Evaristo Gertruda, Hassan Ghada S, Tchervenkov Jean, Shoukry Naglaa H
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, QC, Canada.
Département de Microbiologie, Infectiologie et Immunologie, Faculté de médecine, Université de Montréal, Montréal, QC, Canada.
J Immunol. 2025 Mar 11. doi: 10.1093/jimmun/vkaf014.
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.
肝纤维化是一个全球性的健康问题。白细胞介素-17A（IL-17A）已被证实在肝脏疾病中具有促纤维化特性，使其成为一个有吸引力的治疗靶点。IL-17A受维甲酸相关孤儿受体γt（RORγt）调控，由辅助性T细胞17（Th17）CD4 +细胞和γδ-T细胞产生。我们推测，阻断IL-17A的产生将通过减少炎症细胞的募集来限制纤维化进展。在此，我们在四氯化碳（CCl4）诱导的肝损伤小鼠模型中测试了两种新型RORγt反向激动剂（4,5,6,7-四氢苯并噻吩的2,3衍生物）的治疗潜力。C57BL / 6小鼠每周接受2次CCl4注射，持续4周。从第3周起，小鼠用两种新型反向激动剂（TF-S10和TF-S14）以及作为阳性对照的GSK805进行治疗。用反向激动剂治疗的小鼠在门静脉和中央静脉周围的免疫细胞浸润减少。TF-S14显著降低了天冬氨酸转氨酶（AST）水平（P < 0.05），并且所有抑制剂均使相对肝脏重量（肝脏指数）得到改善。流式细胞术分析表明，所有抑制剂均减少了肝内淋巴细胞（CD4 +、CD8 +和γδ-T细胞，P < 0.05）以及髓样（CD11b +）细胞（P = 0.04）的数量，其中嗜酸性粒细胞减少最为显著（P < 0.05）。此外，CD4 +和γδ-T细胞产生的IL-17A减少（分别为P < 0.05和P < 0.01）。最后，用抑制剂处理的小鼠肝脏显示肝星状细胞激活标志物（结蛋白和α-平滑肌肌动蛋白[α-SMA]）减少，并且促纤维化基因（Col1a1、Acta、Loxl2和Tgfβ）的表达显著降低（P < 0.001）。这伴随着通过天狼星红染色测量的胶原沉积减少（P < 0.001）。总之，我们的结果表明，抑制IL-17A通路可能是治疗肝纤维化的一种有前景的治疗策略。
