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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 Article has an altmetric score of 64

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 6

Expression of Trem1 in liver during fibrogenesis.

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Expression of Trem1 in liver during fibrogenesis.
(A) WT mice were treat...
(A) WT mice were treated with oil (control, n = 3) or a single dose of CCl4 and analyzed after 12 hours and 72 hours (n = 5 mice/time point). Another group of WT mice was treated with 12 injections of CCl4 and analyzed after 6 weeks (n = 7 mice). mRNA levels of Trem1 in liver were assessed by RT-qPCR. Expression was normalized to the average of 3 different control genes (Actb, Gapdh, and Hprt1) and is represented as the fold induction. (B) Representative immunoblot analysis for TREM-1 in WT mouse liver lysates at different time points. β-Actin was used as a loading control. The full, uncut gels are shown in the supplemental material. (C) Quantification of TREM-1 expression in liver from WT control mice (n = 3) and CCl4-treated mice at 12 hours (n = 5), 72 hours (n = 3), and 6 weeks (n = 3). (D) Representative phycoerythrin-conjugated (PE-conjugated) anti–TREM-1 antibody–stained immunofluorescence images of liver sections from WT control oil-injected mice (n = 3, top) and CCl4-treated mice at 12 hours (top), 72 hours, and 6 weeks (n = 5–7 mice/time point/group, bottom). Original magnification, ×20; scale bars: 50 μm. Images are representative of 2 independent experiments. (E) RT-qPCR was performed to assess Trem1 mRNA expression in whole liver as well as in purified hepatocyte, Kupffer cell, and HSC fractions from WT mice (n = 3 mice/cell fraction). (F) Flow cytometric dot plots of WT control mouse liver cells (n = 9 mice) stained with anti-F4/80 and anti-CD11b antibodies. Flow cytometric histograms represent TREM-1 expression on a gated F4/80–CD11b– cell population and on gated F4/80+CD11b– Kupffer cells (n = 9 mice). Control staining was performed with IgG isotype (gray histogram). (G) Flow cytometric dot plots and histograms of TREM-1 expression on gated F4/80+CD11b– Kupffer cells isolated from oil-injected WT control mice (n = 9) and from mice treated with CCl4 (n = 7 mice/time point/group) for 12 hours and 72 hours. Control staining was performed with IgG isotype (gray histogram). (H) Flow cytometric histograms of intracellular expression of IL-1β, TNF, and TGF-β1 on gated F4/80+CD11b– Kupffer cells from CCl4-injured (72 h) WT (n = 4) and Trem1–/– (n = 5) mice. Control staining was performed with IgG isotype (gray histograms). (I) Quantification of mean fluorescence intensity of the indicated cytokines. Results are displayed as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by ANOVA followed by Bonferroni’s post hoc test (A and C) and 2-tailed Student’s t test (I).

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