Format

Send to

Choose Destination
Cell Biochem Biophys. 2015 Nov;73(2):479-487. doi: 10.1007/s12013-015-0682-9.

Neutrophils Play a Crucial Role in the Early Stage of Nonalcoholic Steatohepatitis via Neutrophil Elastase in Mice.

Author information

1
Department of Endocrinology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
2
Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
3
Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
4
Department of Liver Diseases, Xixi Hospital of Hangzhou, Hangzhou, Zhejiang, China.
5
Department of Health Management, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang, China.
6
Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China.
7
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.
8
Center for Translational Medicine, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, China. davidshi0571@126.com.
9
Department of Liver Diseases, The Affiliated Hospital of Hangzhou Normal University, 126 Wenzhou Road, Hangzhou, 310015, Zhejiang, China. davidshi0571@126.com.

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.

KEYWORDS:

Kupffer cells; Neutrophil; Neutrophil elastase; Nonalcoholic steatohepatitis

PMID:
27352342
DOI:
10.1007/s12013-015-0682-9
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center