Selective suppression of M1 macrophages is involved in zinc inhibition of liver fibrosis in mice |
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| Affiliation: | 1. Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China;2. Memphis Institute of Regenerative Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA;1. Linus Pauling Institute, Oregon State University, Corvallis, Oregon;2. Integrative Biology Program, Oregon State University, Corvallis, Oregon;3. Molecular and Cell Biology Program;4. Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon;5. School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon;1. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China;2. Department of Chemistry, Fudan University, Shanghai, China;3. Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China;;4. Center for Gastrointestinal Endoscopy, Shanxi Provincial People''s Hospital, Taiyuan, China.;1. Laboratory of Modified Lipids, Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil;2. Nutritional Genomics and Inflammation Laboratory, Department of Nutrition, School of Public Health, University of São Paulo, São Paulo, Brazil;3. Food Research Center (FoRC), CEPID-FAPESP, Research Innovation and Dissemination Centers São Paulo Research Foundation, São Paulo, Brazil |
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| Abstract: | Zinc deficiency is common in the liver of patients with chronic liver disease. Zinc supplementation suppresses the progression of liver fibrosis induced by bile duct ligation (BDL) in mice. The present study was undertaken to specifically investigate a possible mechanism by which zinc plays this role in the liver. Kunming mice were subjected to BDL for 4 weeks to induce liver fibrosis, and concomitantly treated with zinc sulfite or saline as control by gavage once a day. The results showed that zinc supplementation significantly suppressed liver fibrosis and inflammation along with inhibition of hepatic stellate cells activation induced by BDL. These inhibitory effects were accompanied by the reduction of collagen deposition and a significant reduction of macrophage infiltration affected livers. Importantly, zinc selectively inhibited M1 macrophage polarization and M1-related inflammatory cytokines. This inhibitory effect was further confirmed by the reduction of relevant biomarkers of M1 macrophages including inducible NO synthase (iNOS), monocyte chemotactic protein-1 (MCP-1/CCL2), and tumor necrosis factor-α in the zinc supplemented BDL livers. In addition, zinc inhibition of M1 macrophages was associated with a decrease of Notch1 expression. Taken together, these data indicated that zinc supplementation inhibited liver inflammation and fibrosis in BDL mice through selective suppression of M1 macrophages, which is associated with inhibition of Notch1 pathway in M1 macrophage polarization. |
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