Perforin Acts as an Immune Regulator to Prevent the Progression of NAFLD.

Qian Wang,Jing Zhu,Hua Zhang,Dehai Li,Zhinan Yin,Jianlei Hao,Hengwen Yang,Qiping Shi,Mingyue Zhang,Zonghua Liu,Guangchao Cao,Qiong Wen,Leqing Zhu

doi:10.3389/fimmu.2020.00846

Abstract

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) pathogenesis is tightly linked to obesity and is an emerging healthcare problem worldwide [1, 2]
In the condition of high-fat diet (HFD)-induced NAFLD, we found that Prf−/− mice developed more severe hepatic steatosis with more macrophage and IFN-γ, producing CD4+ T cell infiltration of the liver
Since the level of IFN-γ was significantly increased in the livers of Prf−/− mice, we explored whether CD4 T cells contribute to exacerbated NAFLD in these mice via IFN-γ activity

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) pathogenesis is tightly linked to obesity and is an emerging healthcare problem worldwide [1, 2]. NAFLD, along with related inflammation, progressive subtype non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma, is becoming one of the leading causes of liver-related morbidity and mortality worldwide [3,4,5]. It is appreciated that multiple concurrent intrahepatic and extrahepatic events contribute to development and progression of NAFLD, including cell senescence, insulin resistance, and immune system dysfunction [6, 7]. Recent experimental evidence suggests that hepatocyte senescence is linked to the fibrosis that develops as NAFLD progresses; hepatocyte expression of p21, the universal cell cycle inhibitor, is positively correlated with fibrosis stage in liver sections from 70 NAFLD patients [11]. Inflammation and fibrogenesis are regulated by complex immunologic pathways that may present possible new therapeutic targets in the liver for NAFLD [7]

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Results

Conclusion