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.

In Vitro Human Liver Model of Nonalcoholic Steatohepatitis by Coculturing Hepatocytes, Endothelial Cells, and Kupffer Cells

“…Similar to the results with the Kup5 cells, a significantly higher level of ROS (≈1.9‐fold and ≈2.0‐fold with steatotic conditioned media on day 6 and 8, respectively) was observed in the HKCs when incubated with the steatotic conditioned media for 6 h compared to the healthy conditioned media ( Figure A,B). This is in line with the literature reporting on activated KCs (M1 phenotype) showing higher levels of ROS expression . The morphology of the primary HKCs cultured for 3 h with healthy or steatotic conditioned media from the spheroids on day 6 was also assessed as this specific time point showed the most substantial differences when looking at the morphology changes of Kup5 cells (Figure C and Figure S5, Supporting Information).…”

“…In this work, we hypothesized engineering an in vitro human liver model by coculturing human hepatocytes, endothelial cells, and KCs as spheroids, could be used for understanding the progression from steatosis to NASH with better communications between those different cell types. To verify this hypothesis, HepG2, HUVECs, and HKCs were mixed at a specific ratio (70% HepG2, 15% HUVECs, and 15% HKCs) based on our previous report showing around 80% of HepG2 and 20% of HUVECs could be a better system for the NAFLD pathogenesis as well as this ratio is close to the in vivo percentages of the different cell types . First, to confirm the presence of all three cell types in spheroids, each cell type was incubated with a specific cell tracking dye (red for HepG2, green for HUVECs, and blue for HKCs).…”

Hepatic Stellate Cell–Macrophage Crosstalk in Liver Fibrosis and Carcinogenesis

“…Produced by macrophages PDGF-B, PDGF-C, and D/PDGFR-β pathway contributes to fibrosis progression through HSC proliferation and migration [43][44][45][46][47][48] OSM Produced by macrophages Induces TIMP-1 in HSCs and profibrogenic macrophages, leading to fibrosis progression 117,122 TNF-α TNF-α does not directly induce type I collagen induction in HSCs but contributes to fibrosis by upregulating TIMP-1, downregulating BAMBI, and preventing HSC apoptosis [156][157][158][159] IL-1β Produced by proinflammatory macrophages Contributes to fibrosis through an upregulation of TIMP-1 and downregulation of BAMBI in HSCs 105 and HSC survival 118 Chemokines CCL2 Produced by macrophages and HSCs Promotes macrophage and HSC infiltration and activation through CCR2 97,160,161…”

Comparison of serum biomarkers for the early diagnosis of patients with liver cirrhosis and systemic inflammatory response syndrome

“…Recenty some data demonstrate that the TREM-1 pathway on Kupffer cells plays an essential role in hepatic inflammation and fibrogenesis in a mouse model of fibrosis. TREM-1 controls the mobilization of inflammatory cells in response to injury and consequently enhances liver damage [33]. Maybe we will study the relationship between TREM-1 and severity of liver inflammation in the future.…”