The innate immune receptor TREM-1 promotes liver injury and fibrosis
Anh Thu Nguyen-Lefebvre, Ashwin Ajith, Vera Portik-Dobos, Daniel David Horuzsko, Ali Syed Arbab, Amiran Dzutsev, Ramses Sadek, Giorgio Trinchieri, Anatolij Horuzsko
Anh Thu Nguyen-Lefebvre, Ashwin Ajith, Vera Portik-Dobos, Daniel David Horuzsko, Ali Syed Arbab, Amiran Dzutsev, Ramses Sadek, Giorgio Trinchieri, Anatolij Horuzsko
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Research Article Hepatology Inflammation

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

Abstract

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.

Authors

Anh Thu Nguyen-Lefebvre, Ashwin Ajith, Vera Portik-Dobos, Daniel David Horuzsko, Ali Syed Arbab, Amiran Dzutsev, Ramses Sadek, Giorgio Trinchieri, Anatolij Horuzsko

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Figure 1

Deletion of Trem1 attenuates hepatic fibrogenesis.

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Deletion of Trem1 attenuates hepatic fibrogenesis. (A) Representative ma...
(A) Representative macroscopic images of livers from WT and Trem1–/– control mice (oil-injected, n = 3/group, top) and WT and Trem1–/– mice treated with 12 injections of CCl4 over a 6-week period (n = 6–7/group, bottom). Arrowheads indicate fibrotic nodules visible on CCl4-treated WT mice. (B) Collagen deposition was evaluated with Picrosirius red staining. Representative images of liver sections from WT and Trem1–/– control mice (n = 3/group, top) and from WT and Trem1–/– mice treated with CCl4 (n = 6–7/group, bottom). Original magnification, ×20; scale bars: 50 μm. (C) Quantification (percentage) of Picrosirius red–positive areas. (D) Representative images of liver sections from WT and Trem1–/– control mice (n = 3/group, top) and from WT and Trem1–/– mice treated with CCl4 (n = 5–6/group, bottom) stained with anti–α-SMA antibody. Original magnification, ×10; scale bars: 100 μm. (E) Quantification of α-SMA–positive areas (percentage). (F) Immunoblot analysis of α-SMA in liver lysates from the indicated mice (n = 3/group). β-Actin was used as a loading control. The full, uncut gels are shown in the supplemental material. (G) Quantification of α-SMA expression (n = 3 mice/group). Results are displayed as the mean ± SEM. *P < 0.05, **P < 0.01, and ****P < 0.0001, by 2-tailed Student’s t test (C, E, and G). Experiments shown in A, B, and D are representative of 2 independent experiments.