The role of neutrophils in innate immunity-driven nonalcoholic steatohepatitis: lessons learned and future promise
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REVIEW ARTICLE
The role of neutrophils in innate immunity‑driven nonalcoholic steatohepatitis: lessons learned and future promise Lihong Wu1,2 · Xiang Gao1,2 · Qianyu Guo1,2 · Jufei Li1,2 · Jianyu Yao1,2 · Kaixuan Yan1,2 · Ying Xu3 · Xue Jiang1,2 · Dewei Ye1,2 · Jiao Guo1,2 Received: 20 April 2020 / Accepted: 17 August 2020 © Asian Pacific Association for the Study of the Liver 2020
Abstract The enrichment of innate immune cells and the enhanced inflammation represent the hallmark of non-alcoholic steatohepatitis (NASH), the advanced subtype with a significantly increased risk of progression to end-stage liver diseases within the spectrum of non-alcoholic fatty liver disease. Neutrophils are traditionally recognized as key components in the innate immune system to defend against pathogens. Recently, a growing body of evidence supports neutrophils as emerging key player in mediating the transition from steatosis to NASH, which is largely inspired by the histological findings in human liver biopsy indicating the enhanced infiltration of neutrophils as one of the key histological features of NASH. In this review, we discuss data regarding histological perspectives of hepatic infiltration of neutrophils in NASH. We also highlight the pathophysiological role of neutrophils in promoting metabolic inflammation in the liver through the release of a vast array of granule proteins, the interaction with other pro-inflammatory immune cells, and the formation of neutrophil extracellular traps. Neutrophil granule proteins possess pleiotropic effects on regulating neutrophil biology and functions. A variety of granule proteins (including lipocalin-2, myeloperoxidase, proteinase 3, neutrophil elastase, etc.) produced by neutrophils enhance liver metabolic inflammation, thereby promoting NASH progression by mediating neutrophil-macrophage interaction. Therapeutically, pharmacological inhibitors targeting neutrophil granule proteins hold promise to combat NASH. In addition, this article also summarizes potentials of neutrophils and its derived various granule proteins for the accurate, even non-invasive diagnosis of NASH. Graphic abstract
Keywords NASH · Liver inflammation · Neutrophil granule proteins · Neutrophil extracellular traps · Macrophages · Innate immunity · Fatty liver · Neutrophil-macrophage axis · Biomarkers · Serine protease * Dewei Ye [email protected] * Jiao Guo [email protected] Extended author information available on the last page of the article
Abbreviations ALD Alcoholic liver disease CCL CC-chemokine ligand CXCL CXC-chemokine ligand CXCR CXC chemokine/motif receptor
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DCs Dendritic cells ECM Extracellular matrix G-CSF Granulocyte colony stimulating factor HSCs Hepatic stellate cells IL-1α Interleukin-1α LCN2 Lipocalin-2 LPS Lipopolysaccharide Ly6G Lymphocyte antigen 6 complex locus G6D MCD Methionine- and choline-deficient MPO Myeloperoxidase NAFLD Nonalcoholic fatty liver disease NASH Non-alcoholic steatohepatitis NE Neutrophil elastase NET Neutrophil extracel
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