한빛사논문
- 조회2,691
Seonghwan Hwang,1 Yong He,1 Xiaogang Xiang,1 Wonhyo Seo,1 Seung-Jin Kim,1 Jing Ma,1 Tianyi Ren,1 Seol Hee Park,1 Zhou Zhou,1 Dechun Feng,1 George Kunos,2 Bin Gao1,*
1 Laboratory of Liver Diseases, 2Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
* Corresponding author: Bin Gao, M.D., Ph.D., Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892
Abstract
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. Here we demonstrate that overexpression of Cxcl1 in the liver alone promotes steatosis‐to‐NASH progression in HFD‐fed mice by inducing neutrophil infiltration, oxidative stress, and stress kinase (such as ASK1 and p38MAPK) activation. Myeloid cell‐specific deletion of the neutrophil cytosolic factor 1 (Ncf1)/p47phox 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 inflammation in NASH.
Conclusion
Hepatic overexpression of CXCL1 is sufficient to drive steatosis‐to‐NASH progression in HFD‐fed mice through neutrophil‐derived reactive oxygen species and activation of stress kinases, which can be reversed by IL‐22 treatment via the induction of metallothionein.
Keywords : Inflammation, extracellular vesicles, oxidative stress, mitochondrial DNA
논문정보
- Research article
- 2019년 11월 (BRIC 등록일 2019-11-18)
- 국외 연구진
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