Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada; Département de Département de Pathologie et Biologie Cellulaire, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
Cell Mol Gastroenterol Hepatol. 2022;14(6):1269-1294. doi: 10.1016/j.jcmgh.2022.08.001. Epub 2022 Aug 13.
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is a major health problem with complex pathogenesis. Although sex differences in NAFLD pathogenesis have been reported, the mechanisms underlying such differences remain understudied. Interleukin (IL)22 is a pleiotropic cytokine with both protective and/or pathogenic effects during liver injury. IL22 was shown to be hepatoprotective in NAFLD-related liver injury. However, these studies relied primarily on exogenous administration of IL22 and did not examine the sex-dependent effect of IL22. Here, we sought to characterize the role of endogenous IL22-receptor signaling during NAFLD-induced liver injury in males and females.
We used immunofluorescence, flow cytometry, histopathologic assessment, and gene expression analysis to examine IL22 production and characterize the intrahepatic immune landscape in human subjects with NAFLD (n = 20; 11 men and 9 women) and in an in vivo Western high-fat diet-induced NAFLD model in IL22RA knock out mice and their wild-type littermates.
Examination of publicly available data sets from 2 cohorts with NAFLD showed increased hepatic IL22 gene expression in females compared with males. Furthermore, our immunofluorescence analysis of liver sections from NAFLD subjects (n = 20) showed increased infiltration of IL22-producing cells in females. Similarly, IL22-producing cells were increased in wild-type female mice with NAFLD and the hepatic IL22/IL22 binding protein messenger RNA ratio correlated with expression of anti-apoptosis genes. The lack of endogenous IL22-receptor signaling (IL22RA knockout) led to exacerbated liver damage, inflammation, apoptosis, and liver fibrosis in female, but not male, mice with NAFLD.
Our data suggest a sex-dependent hepatoprotective antiapoptotic effect of IL22-receptor signaling during NAFLD-related liver injury in females.
非酒精性脂肪性肝病（NAFLD）是一种具有复杂发病机制的主要健康问题。尽管已经报道了 NAFLD 发病机制中的性别差异，但这些差异的机制仍研究不足。白细胞介素（IL）22 是一种具有多种功能的细胞因子，在肝损伤时有保护和/或致病作用。IL22 在与 NAFLD 相关的肝损伤中被证明具有肝保护作用。然而，这些研究主要依赖于外源性给予 IL22，并未检测 IL22 的性别依赖性效应。在此，我们试图描述内源性 IL22 受体信号在雄性和雌性 NAFLD 诱导的肝损伤中的作用。
我们使用免疫荧光、流式细胞术、组织病理学评估和基因表达分析来检查 IL22 的产生，并描述 NAFLD 患者（n=20；11 名男性和 9 名女性）和 IL22RA 敲除小鼠及其野生型同窝仔鼠的体内 Western 高脂肪饮食诱导的 NAFLD 模型中的肝内免疫景观。
检查来自 2 个 NAFLD 队列的公开数据集显示，与男性相比，女性肝内 IL22 基因表达增加。此外，我们对 NAFLD 患者（n=20）肝组织切片的免疫荧光分析显示，女性 IL22 产生细胞浸润增加。同样，在患有 NAFLD 的野生型雌性小鼠中，IL22 产生细胞增加，且肝内 IL22/IL22 结合蛋白信使 RNA 比值与抗凋亡基因的表达相关。缺乏内源性 IL22 受体信号（IL22RA 敲除）导致雌性而非雄性 NAFLD 小鼠的肝损伤、炎症、细胞凋亡和肝纤维化加剧。
我们的数据表明，在与 NAFLD 相关的肝损伤中，IL22 受体信号具有性别依赖性的抗凋亡作用。
