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

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.

• Authors: Xiang Zhang, Juqiang Han, Kwan Man, Xiaoxing Li, Jinghua Du, Eagle S H Chu, Minnie Y Y Go, Joseph J Y Sung, Jun Yu
• Journal: Journal of hepatology (J Hepatol) Vol. 64 Issue 1 Pg. 160-70 (Jan 2016) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 26394162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

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

Topics

• 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)