Centre de Recherche du Centre hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.
Département de microbiologie, infectiologie et immunologie, Faculté de médecine, Université de Montréal, Montréal, Québec, Canada.
Sci Immunol. 2018 Oct 26;3(28). doi: 10.1126/sciimmunol.aar7754.
Inflammatory immune cells can modulate activation of hepatic stellate cells (HSCs) and progression of liver fibrosis. Type 3 inflammation characterized by production of interleukin-17A (IL-17) and IL-22 by innate and adaptive immune cells is implicated in many inflammatory conditions of the gut and can be counteracted by regulatory T cells (T), but its contribution to liver fibrosis is still poorly understood. Here, we evaluated the contribution of type 3 inflammation in liver fibrosis using clinical liver biopsies, in vitro stimulation of primary HSCs, and in vivo mouse models. We report dysregulated type 3 responses in fibrotic lesions with increased IL-17CD4/FOXP3CD4 ratio and increased IL-17 and IL-22 production in advanced liver fibrosis. Neutrophils and mast cells were the main sources of IL-17 in situ in humans. In addition, we demonstrate a new profibrotic function of IL-22 through enhancement of transforming growth factor-β signaling in HSCs in a p38 mitogen-activated protein kinase-dependent manner. In vivo, IL-22RA1 knockout mice exhibited reduced fibrosis in response to thioacetamide and carbon tetrachloride. Blocking either IL-22 or IL-17 production using aryl hydrocarbon receptor or RAR-related orphan receptor gamma-t antagonists resulted in reduced fibrosis. Together, these data have identified a pathogenic role for type 3 immune response mediated by IL-22 in driving liver fibrosis during chronic liver injury.
炎症免疫细胞可以调节肝星状细胞（HSCs）的激活和肝纤维化的进展。由先天和适应性免疫细胞产生白细胞介素-17A（IL-17）和白细胞介素-22 的 3 型炎症与肠道的许多炎症状态有关，并且可以被调节性 T 细胞（T）所抵消，但它对肝纤维化的贡献仍知之甚少。在这里，我们使用临床肝活检、原代 HSCs 的体外刺激和体内小鼠模型评估了 3 型炎症在肝纤维化中的作用。我们报告了纤维化病变中 3 型反应失调，表现为 IL-17CD4/FOXP3CD4 比值增加，晚期肝纤维化中 IL-17 和 IL-22 产生增加。中性粒细胞和肥大细胞是人类原位 IL-17 的主要来源。此外，我们通过 p38 丝裂原激活蛋白激酶依赖性方式证明了 IL-22 在 HSCs 中增强转化生长因子-β信号的新的促纤维化功能。在体内，IL-22RA1 基因敲除小鼠对硫代乙酰胺和四氯化碳的纤维化反应减少。使用芳烃受体或 RAR 相关孤儿受体 γt 拮抗剂阻断 IL-22 或 IL-17 的产生可减少纤维化。总之，这些数据表明，由 IL-22 介导的 3 型免疫反应在慢性肝损伤期间驱动肝纤维化中具有致病性作用。
