Interleukin‐22 Ameliorates Neutrophil‐Driven Nonalcoholic Steatohepatitis Through Multiple Targets

作者：Seonghwan Hwang, Yong He, Xiaogang Xiang, Wonhyo Seo, Seung‐Jin Kim, Jing Ma, Tianyi Ren, Seol Hee Park, Zhou Zhou, Dechun Feng, George Kunos, Bin Gao · 发表于：Hepatology · 年份：2019 · DOI：10.1002/hep.31031 · 被引用次数：179 · 研究领域：Liver Disease Diagnosis and Treatment、Liver Diseases and Immunity、Adipokines, Inflammation, and Metabolic Diseases

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, and liver cancer. At present, how simple steatosis progresses to NASH remains obscure and effective pharmacological therapies are lacking. Hepatic expression of C-X-C motif chemokine ligand 1 (CXCL1), a key chemokine for neutrophil infiltration (a hallmark of NASH), is highly elevated in NASH patients but not in fatty livers in obese individuals or in high-fat diet (HFD)-fed mice. The aim of this study was to test whether overexpression of CXCL1 itself in the liver can induce NASH in HFD-fed mice and to test the therapeutic potential of IL-22 in this new NASH model. APPROACH AND RESULTS: gene, which encodes a component of the NADPH oxidase 2 complex that mediates neutrophil oxidative burst, markedly reduced CXCL1-induced NASH and stress kinase activation in HFD-fed mice. Treatment with interleukin (IL)-22, a cytokine with multiple targets, ameliorated CXCL1/HFD-induced NASH or methionine-choline deficient diet-induced NASH in mice. Mechanistically, IL-22 blocked hepatic oxidative stress and its associated stress kinases via the induction of metallothionein, one of the most potent antioxidant proteins. Moreover, although it does not target immune cells, IL-22 treatment attenuated the inflammatory functions of hepatocyte-derived, mitochondrial DNA-enriched extracellular vesicles, thereby suppressing liver infla...