CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy

Xiang Zhang; Juqiang Han; Kwan Man; Xiaoxing Li; Jinghua Du; Eagle S H Chu; Minnie Y Y Go; Joseph J Y Sung; Jun Yu

doi:10.1016/j.jhep.2015.09.005

CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy

J Hepatol. 2016 Jan;64(1):160-70. doi: 10.1016/j.jhep.2015.09.005. Epub 2015 Sep 21.

Authors

Xiang Zhang¹, Juqiang Han², Kwan Man³, Xiaoxing Li⁴, Jinghua Du⁵, Eagle S H Chu¹, Minnie Y Y Go¹, Joseph J Y Sung¹, Jun Yu⁶

Affiliations

¹ Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
² Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Institute of Liver Disease, Beijing Military General Hospital, Beijing, China.
³ Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong.
⁴ Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
⁵ Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.
⁶ Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong. Electronic address: junyu@cuhk.edu.hk.

PMID: 26394162
DOI: 10.1016/j.jhep.2015.09.005

Abstract

Background & aims: CXC chemokine receptor 3 (CXCR3) is involved in virus-related chronic liver inflammation. However, the role of CXCR3 in non-alcoholic steatohepatitis (NASH) remains unclear. We aimed to investigate the role of CXCR3 in NASH.

Methods: Human liver tissues were obtained from 24 non-alcoholic fatty liver disease (NAFLD) patients and 20 control subjects. CXCR3 knockout (CXCR3(-/-)), obese db/db mice and their wild-type (WT) littermates were used in both methionine-and-choline-deficient (MCD) diet and high-fat high-carbohydrate high-cholesterol (HFHC) diet-induced NASH models. In addition, MCD-fed WT mice were administrated with CXCR3 specific antagonists.

Results: CXCR3 was significantly upregulated in liver tissues of patients with NAFLD and in dietary-induced NASH animal models. Compared with WT littermates, CXCR3(-/-) mice were more resistant to both MCD and HFHC diet-induced steatohepatitis. Induction of CXCR3 in dietary-induced steatohepatitis was associated with the increased expression of hepatic pro-inflammatory cytokines, activation of NF-κB, macrophage infiltration and T lymphocytes accumulation (Th1 and Th17 immune response). CXCR3 was also linked to steatosis through inducing hepatic lipogenic genes. Moreover, CXCR3 is associated with autophagosome-lysosome impairment and endoplasmic reticulum (ER) stress in steatohepatitis as evidenced by LC3-II and p62/SQSTM1 accumulation and the induction of GRP78, phospho-PERK and phospho-eIF2α. Inhibition of CXCR3 using CXCR3 antagonist significantly suppressed MCD-induced steatosis and hepatocytes injury in AML-12 hepatocytes. Blockade of CXCR3 using CXCR3 antagonists in mice reversed the established steatohepatitis.

Conclusions: CXCR3 plays a pivotal role in NASH development by inducing production of cytokines, macrophage infiltration, fatty acid synthesis and causing autophagy deficiency and ER stress.

Keywords: Animal model; Autophagy; CXCR3; Macrophage; Non-alcoholic steatohepatitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy / physiology*
Choline Deficiency / immunology
Cytokines / physiology*
Endoplasmic Reticulum Chaperone BiP
Endoplasmic Reticulum Stress
Humans
Lipogenesis
Macrophages / physiology*
Male
Methionine / deficiency
Mice
Mice, Inbred C57BL
NF-kappa B / physiology
Non-alcoholic Fatty Liver Disease / etiology*
Receptors, CXCR3 / physiology*
Th1 Cells / immunology
Th17 Cells / immunology

Substances

CXCR3 protein, human
Cxcr3 protein, mouse
Cytokines
Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
Hspa5 protein, mouse
NF-kappa B
Receptors, CXCR3
Methionine