The innate immune receptor TREM-1 promotes liver injury and fibrosis

• Published in: The Journal of clinical investigation Vol. 128; no. 11; pp. 4870 - 4883
• Main Authors: Nguyen-Lefebvre, Anh Thu, Ajith, Ashwin, Portik-Dobos, Vera, Horuzsko, Daniel David, Arbab, Ali Syed, Dzutsev, Amiran, Sadek, Ramses, Trinchieri, Giorgio, Horuzsko, Anatolij
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-11-2018
• Subjects: Animals; Bile; Biomedical research; Carbon; Carbon tetrachloride; CCL4 protein; Cell activation; Chemokines; Chronic Disease; Clonal deletion; Cytokines - genetics; Cytokines - immunology; Female; Fibrosis; Gene Expression Regulation - immunology; Hepatitis; Hepatocytes; Hepatology; Humans; Infections; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Kupffer cells; Kupffer Cells - immunology; Kupffer Cells - pathology; Liver - immunology; Liver - injuries; Liver - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - immunology; Liver Cirrhosis - pathology; Liver diseases; Macrophages; Male; Mice; Mice, Mutant Strains; Monocytes; Monocytes - immunology; Monocytes - pathology; Myeloid cells; Nanoparticles; Neutrophils; Rodents; Stellate cells; Triggering Receptor Expressed on Myeloid Cells-1 - genetics; Triggering Receptor Expressed on Myeloid Cells-1 - immunology; Viral infections; Hepatology; Inflammation; Fibrosis
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI98156

Inflammation occurs in all tissues in response to injury or stress and is the key process underlying hepatic fibrogenesis. Targeting chronic and uncontrolled inflammation is one strategy to prevent liver injury and fibrosis progression. Here, we demonstrate that triggering receptor expressed on myeloid cells 1 (TREM-1), an amplifier of inflammation, promotes liver disease by intensifying hepatic inflammation and fibrosis. In the liver, TREM-1 expression was limited to liver macrophages and monocytes and was highly upregulated on Kupffer cells, circulating monocytes, and monocyte-derived macrophages in a mouse model of chronic liver injury and fibrosis induced by carbon tetrachloride (CCl4) administration. TREM-1 signaling promoted proinflammatory cytokine production and mobilization of inflammatory cells to the site of injury. Deletion of Trem1 reduced liver injury, inflammatory cell infiltration, and fibrogenesis. Reconstitution of Trem1-deficient mice with Trem1-sufficient Kupffer cells restored the recruitment of inflammatory monocytes and the severity of liver injury. Markedly increased infiltration of liver fibrotic areas with TREM-1-positive Kupffer cells and monocytes/macrophages was found in patients with hepatic fibrosis. Our data support a role of TREM-1 in liver injury and hepatic fibrogenesis and suggest that TREM-1 is a master regulator of Kupffer cell activation, which escalates chronic liver inflammatory responses, activates hepatic stellate cells, and reveals a mechanism of promotion of liver fibrosis.