Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD
Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD
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穿孔素作为免疫调节剂来预防 NAFLD 的进展
DOI：
10.3389/fimmu.2020.00846
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发表时间：
2020-05-22
影响因子：
7.3
通讯作者：
Yin，Zhinan
中科院分区：
文献类型：
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作者：
Wang，Qian;Li，Dehai;Yin，Zhinan
非酒精性脂肪性肝病(NAFLD)是引起肝硬变的主要原因之一，也是肝细胞癌和肝脏相关死亡的主要危险因素。尽管进行了大量的临床和基础研究，但肥胖相关的NAFLD的发病机制仍然知之甚少。在这项研究中，我们证明穿孔素可以作为一种免疫调节剂来防止NAFLD的进展。与WT小鼠相比，老年穿孔素缺乏(PrF−/−)小鼠肝脏中的脂肪堆积增加。与WT对照组相比，与WT对照组相比，高脂饮食挑战下，PrF−/−小鼠的肝脏重量增加，肝脏损伤更严重，肝脏炎症增加。机制研究表明，穿孔素特异性地调节CD4T细胞而不是CD8T细胞内固有的干扰素-γ的产生。我们发现，CD4T细胞去除可以减轻−/−小鼠的肝脏损伤，改善炎症和代谢性疾病。此外，在HFD PRF−/−和干扰素-γR−/−双基因敲除小鼠中，肝脏特征的改善证实了干扰素-γ是介导穿孔素调节非酒精性脂肪肝进展的关键因素。总体而言，我们的发现揭示了穿孔素在肥胖相关NAFLD的进展中所起的重要调节作用，并突出了治疗NAFLD的新策略。
Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of cirrhosis and major risk factors for hepatocellular carcinoma and liver-related death. Despite substantial clinical and basic research, the pathogenesis of obesity-related NAFLD remains poorly understood. In this study, we show that perforin can act as an immune regulator to prevent the progression of NAFLD. Aged perforin-deficient (Prf−/−) mice have increased lipid accumulation in the liver compared to WT mice. With high-fat diet (HFD) challenge, Prf−/− mice have increased liver weight, more severe liver damage, and increased liver inflammation when compared with WT controls. Mechanistic studies revealed that perforin specifically regulates intrinsic IFN-γ production in CD4 T cells, not CD8 T cells. We found that CD4 T cell depletion reduces liver injury and ameliorates the inflammation and metabolic morbidities in Prf−/− mice. Furthermore, improved liver characteristics in HFD Prf−/− and IFN-γR−/− double knockout mice confirmed that IFN-γ is a key factor for mediating perforin regulation of NAFLD progression. Overall, our findings reveal the important regulatory role perforin plays in the progression of obesity-related NAFLD and highlight novel strategies for treating NAFLD.