Inhibition of Triggering Receptor Expressed on Myeloid Cells 1 Ameliorates Inflammation and Macrophage and Neutrophil Activation in Alcoholic Liver Disease in Mice

Abstract

Alcoholic liver disease (ALD) is characterized by macrophage and neutrophil leukocyte recruitment and activation in the liver. Damage‐ and pathogen‐associated molecular patterns contribute to a self‐perpetuating proinflammatory state in ALD. Triggering receptor expressed on myeloid cells 1 (TREM‐1) is a surface receptor that amplifies inflammation induced by toll‐like receptors (TLRs) and is expressed on neutrophils and monocytes/macrophages. We hypothesized that TREM‐1 signaling contributes to proinflammatory pathway activation in ALD. Using an in vivo ALD model in mice, we tested the effects of ligand‐independent TREM‐1 inhibitory peptides that were formulated into human high‐density lipoprotein (HDL)‐mimicking complexes GF9‐HDL and GA/E31‐HDL. As revealed in vitro, macrophages endocytosed these rationally designed complexes through scavenger receptors. A 5‐week alcohol feeding with the Lieber‐DeCarli diet in mice resulted in increased serum alanine aminotransferase (ALT), liver steatosis, and increased proinflammatory cytokines in the liver. TREM‐1 messenger RNA (mRNA) expression was significantly increased in alcohol‐fed mice, and TREM‐1 inhibitors significantly reduced this increase. TREM‐1 inhibition significantly attenuated alcohol‐induced spleen tyrosine kinase (SYK) activation, an early event in both TLR4 and TREM‐1 signaling. The TREM‐1 inhibitors significantly inhibited macrophage (epidermal growth factor‐like module‐containing mucin‐like hormone receptor‐like 1 [F4/80], clusters of differentiation [CD]68) and neutrophil (lymphocyte antigen 6 complex, locus G [Ly6G] and myeloperoxidase [MPO]) markers and proinflammatory cytokines (monocyte chemoattractant protein 1 [MCP‐1], tumor necrosis factor α [TNF‐α], interleukin‐1β [IL‐1β], macrophage inflammatory protein 1α [MIP‐1α]) at the mRNA level compared to the HDL vehicle. Administration of TREM‐1 inhibitors ameliorated liver steatosis and early fibrosis markers (α‐smooth muscle actin [αSMA] and procollagen1α [Pro‐Col1α]) at the mRNA level in alcohol‐fed mice. However, the HDL vehicle also reduced serum ALT and some cytokine protein levels in alcohol‐fed mice, indicating HDL‐related effects. Conclusion: HDL‐delivered novel TREM‐1 peptide inhibitors ameliorate early phases of inflammation and neutrophil and macrophage recruitment and activation in the liver and attenuate hepatocyte damage and liver steatosis. TREM‐1 inhibition represents a promising therapeutic approach for further investigations in ALD.

The Role of Myeloid-Derived Cells in the Progression of Liver Disease

“…However, dysbiosis and translocation of gut bacteria and bacterial products due to intestinal barrier dysfunction result in the excessive presence of PAMPs within the hepatic microvasculature that reach the liver via the portal vein (195) which, in murine models, drives inflammasome activation of profibrotic hepatic stellate cells (196, 197). In a recent publication the cell-specific innate immune receptor triggering receptor expressed on myeloid cells-1 (TREM-1) was reported to promote hepatic inflammation and fibrosis in mice and humans (198), and inhibition of TREM-1 in mice ameliorated inflammation and macrophage and neutrophil activation in a mouse model of ARLD (199).…”

Morin Hydrate Inhibits Influenza Virus entry into Host Cells and Has Anti-inflammatory Effect in Influenza-infected Mice

“…In this study, we observed that mice treated with morin hydrate showed decreased levels of pro-inflammatory cytokines in lungs during influenza infection, which may be associated with its effects on immune cells, in addition to direct inhibition of influenza virus entry. It reduced the expression of LPS-induced TNF-α and IL-1β in RAW264.7 macrophage cell line ( 10 ) and also inhibited TREM-1, which is highly expressed receptor in neutrophils, monocytes and macrophages ( 38 39 40 ). However, further studies are needed to understand whether the anti-viral effects of morin hydrate are mediated through modulation of immune cell activation, or solely through the inhibition of influenza virus entry.…”

Myricetin Modulates Macrophage Polarization and Mitigates Liver Inflammation and Fibrosis in a Murine Model of Nonalcoholic Steatohepatitis

“…Interestingly, a recent study suggested that TREM-1 receptor also mediated in reversing M2 polarization induced by hypoxia (18). Although the specific ligands of TREM-1 have not been identified yet, it has been revealed that TREM-1 activation amplifies the TLR2/4-mediated proinflammatory signals, allowing the secretion of proinflammatory chemokines and cytokine (14,17). Moreover, recent studies have demonstrated that TREM-1 mediated signaling modulation of M1 macrophage activation promoted the inflammatory response in alcoholic liver disease and obesity-induced fatty liver disease (18,20).…”

“…Upon activation, TREM-1 can trigger and augment inflammatory reaction, especially through synergism with toll-like receptors (TLRs) signaling in macrophages (13)(14)(15)(16). Moreover, several studies have already revealed that TREM-1 play an important role in regulating the activation of Kupffer cell and is associated with macrophages polarization, which amplifies acute and chronic inflammatory responses in diseases (17)(18)(19). Interestingly, a recent report has demonstrated that overexpression of TREM-1 in the liver and M1 hepatic macrophages polarization were associated with obesity-induced insulin resistance (IR) (20).…”