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

• Published in: Journal of hepatology Vol. 64; no. 1; pp. 160 - 170
• Main Authors: Zhang, Xiang, Han, Juqiang, Man, Kwan, Li, Xiaoxing, Du, Jinghua, Chu, Eagle S.H., Go, Minnie Y.Y., Sung, Joseph J.Y., Yu, Jun
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2016
• Subjects: Animal model; Animals; Autophagy; Autophagy - physiology; Choline Deficiency - immunology; CXCR3; Cytokines - physiology; Endoplasmic Reticulum Stress; Gastroenterology and Hepatology; Humans; Lipogenesis; Macrophage; Macrophages - physiology; Male; Methionine - deficiency; Mice; Mice, Inbred C57BL; NF-kappa B - physiology; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic steatohepatitis; Receptors, CXCR3 - physiology; Th1 Cells - immunology; Th17 Cells - immunology; Animal model; NAFLD; MCP-1; LXR; ICAM-1; FACS; Autophagy; α-SMA; TUNEL; CXCR3; CCL4; HFHC; UPS; Non-alcoholic steatohepatitis; WT; IL; SCD-1; NASH; ER; SREBP-1c; MCD; TNF-α; FAS; LAMP; Macrophage; Terminal deoxynucleotidyl transferase dUTP nick end labeling; non-alcoholic fatty liver disease; stearoly-CoA desaturase isoform-1; fluorescence-activated cell sorter; high-fat high-carbohydrate high-cholesterol; CCL 4; sterol regulatory element binding protein isoform 1c; tumor necrosis factor alpha; CXC chemokine receptor 3; monocyte chemoattractant protein 1; liver X receptors; interleukin; intercellular adhesion molecule-1; alpha-smooth muscle actin; methionine-and-choline-deficient; carbon tetrachloride; ubiquitin-proteasome system; CXCR3 knockout; fatty acid synthase; lysosome-associated membrane protein; wild-type; endoplasmic reticulum; non-alcoholic steatohepatitis
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2015.09.005

[Display omitted] 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. 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. 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. 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.