title: Neutrophils Play a Crucial Role in the Early Stage of Nonalcoholic Steatohepatitis via Neutrophil Elastase in Mice.
abstract: Neutrophils infiltration in liver is one of the typical histological characteristics of nonalcoholic steatohepatitis (NASH) in both animal models and human subjects. This study was aimed to investigate the role of neutrophils in the process of NASH and its underling mechanisms. C57BL/6J mice were fed with either standard chow (SC) or methionine/choline-deficient (MCD) diet for 1, 2, 4, 8 weeks, respectively. C57BL/6J APOE(-/-) mice were fed with SC or high-fat high-cholesterol (HFHC) diet. Anti-Ly6G antibody was employed to deplete neutrophils and sivelestat was used to inhibit neutrophil elastase (NE). MCD-diet-receiving mice with neutrophil depletion had much lower serum ALT activity, liver inflammation, and mRNA levels of proinflammatory genes in the early stage of NASH (1 and 2 weeks) when compared to non-neutrophil-depleted mice. NE inhibitor sivelestat could recapitulate the effects of neutrophil depletion in APOE(-/-) mice fed with HFHC diet. As the disease progressed (4 and 8 weeks), neutrophil depletion did not lower serum ALT levels and liver lesions due to activation of Kupffer cells. Finally, we found neutrophils also affected anti-inflammation cytokine interleukin-1 receptor antagonist mRNA expression. Neutrophils play a crucial role in the early stage of NASH via NE.
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.|Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
authors.forename: Shufei
authors.initials: S
authors.lastname: Zang
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Geli
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Zhuang
authors.affiliation: Department of Liver Diseases, Xixi Hospital of Hangzhou, Hangzhou, Zhejiang, China.
authors.forename: Yunhao
authors.initials: Y
authors.lastname: Xun
authors.affiliation: Department of Health Management, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Falin
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
authors.forename: Yinlan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, Faculty of Medicine, The University of Hong Kong, Room L8-33A, Lab Block, 21 Sassoon Road, Hong Kong, China. drdeweiye@163.com.
authors.forename: Dewei
authors.initials: D
authors.lastname: Ye
authors.affiliation: Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China. davidshi0571@126.com.|Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou, 310015, Zhejiang, China. davidshi0571@126.com.
authors.forename: Junping
authors.initials: J
authors.lastname: Shi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005998:Glycine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D007728:Kupffer Cells / Q000166:cytology / Q000378:metabolism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D000410:Alanine Transaminase; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001057:Apolipoproteins E; D018932:Chemokine CCL2; D005998:Glycine; D053590:Interleukin 1 Receptor Antagonist Protein; D019272:Leukocyte Elastase; D012333:RNA, Messenger; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C491768:Ccl2 protein, mouse; C069195:sivelestat
keywords: Kupffer cells; Neutrophil; Neutrophil elastase; Nonalcoholic steatohepatitis