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The innate immune receptor TREM-1 promotes liver injury and fibrosis
Anh Thu Nguyen-Lefebvre, … , Giorgio Trinchieri, Anatolij Horuzsko
Anh Thu Nguyen-Lefebvre, … , Giorgio Trinchieri, Anatolij Horuzsko
Published August 23, 2018
Citation Information: J Clin Invest. 2018;128(11):4870-4883. https://doi.org/10.1172/JCI98156.
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Research Article Hepatology Inflammation

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

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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 8

Increased TREM-1–, CD11b-, and CD68-positive cell infiltration in human liver samples from patients diagnosed with advanced fibrosis.

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Increased TREM-1–, CD11b-, and CD68-positive cell infiltration in human ...
(A) Representative images of human liver samples from a control subject (Metavir = F0, n = 6) and a patient diagnosed with advanced fibrosis (Metavir = F3/F4, n = 4). Samples were stained with Masson’s trichrome to assess collagen deposition. Original magnification, ×10; scale bars: 100 μm. (B) Quantification (percentage) of Masson’s trichrome–positive areas in liver samples from a control subject (n = 10 areas) and a patient with advanced fibrosis (n = 13 areas). (C) Fluorescence multiplexed IHC of human liver samples. Samples from a control subject and a patient with advanced fibrosis were stained for α-SMA (red), TREM-1 (green), and DAPI (blue). Original magnification, ×20; scale bars: 50 μm. (D) Quantification of α-SMA–positive cells (percentage) from a control subject and a patient with advanced fibrosis (n = 10 areas vs. n = 15 areas, respectively. (E) Quantification (percentage) of TREM-1–positive cells from a control subject and a patient with advanced fibrosis (n = 9 and n= 14 areas, respectively). (F) Samples from a control subject and a patient with advanced fibrosis were stained for CD11b (orange), CD68 (magenta), TREM-1 (green), and DAPI (blue). Original magnification, ×20; scale bars: 50 μm. (G) Quantification (percentage) of CD11b-positive cells from a control subject and a patient with advanced fibrosis (n = 10 vs. n = 15 areas, respectively). (H) Quantification (percentage) of CD68-positive cells from a control subject and a patient with advanced fibrosis (n = 8 and n = 12 areas, respectively). Data are displayed as the mean ± SEM. ****P < 0.0001, by 2-tailed Student’s t test (B, D, E, G, and H).
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