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.
View: Text | PDF
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

×

Figure 7

Adoptive transfer of Kupffer cells from WT mice increases liver injury and recruitment of inflammatory cells in Trem1–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Adoptive transfer of Kupffer cells from WT mice increases liver injury a...
(A) Representative images of FITC-conjugated anti-F4/80 antibody–stained liver sections from the indicated mice 72 hours after injection of clodronate-containing liposomes (n = 3 mice/group, top), followed by reconstitution of predepleted livers with WT Kupffer cells (n = 3 mice/group). Adoptively transferred cells were observed at 72 hours by immunofluorescence staining. Original magnification, ×40; scale bars: 20 μm. Images shown are representative of 2 independent experiments. Levels of (B) ALT and (C) AST in serum from WT and Trem1–/– mice with adoptive transfer of WT Kupffer cells followed by a single dose of CCl4 treatment were measured 72 hours after CCl4 injury by colorimetric assay (n = 3–5 mice/group). (D) Macrophage-depleted WT and Trem1–/– mice were adoptively transferred with WT Kupffer cells following treatment with a single dose of CCl4. Flow cytometric dot plots of liver cells stained with anti-F4/80, anti-CD11b, anti-TNF, anti–TGF-β1, anti-Ly6C, anti-Ly6G, anti-CCR2, and anti-CX3CR1 antibodies (n = 3 mice/group). Flow cytometric histograms of Ly6C, Ly6G, CCR2, and CX3CR1 expression shown on gated F4/80+CD11b+ and F4/80–CD11b+ cells (n = 3 mice/group). Control staining was performed with IgG isotype (gray histograms). Mean fluorescence intensity of TNF (E) and TGF-β1 (F) in the indicated mice is shown for gated F4/80+CD11b– Kupffer cells (n = 3 mice/group). (G and H) Percentage of liver-infiltrated neutrophils and inflammatory monocytes under the indicated experimental conditions in WT and Trem1–/– mice (n = 3–7/group). Results are displayed as the mean ± SEM. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-tailed Student’s t test (B, C, E, and F) and ANOVA followed by Bonferroni’s post hoc test (G and H). AT, adoptive transfer.