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

Tornai, David; Furi, Istvan; Shen, Zu T.; Sigalov, Alexander B.; Coban, Sahin; Szabo, Gyongyi

In this study, we report for the first time an important role for TREM-1 in ALD. Using a mouse model, we found a significant up-regulation of TREM-1 in livers of mice following chronic alcohol feeding. Treatment with novel ligand-independent TREM-1 inhibitors reduced the expression of the TREM-1 molecule itself, attenuated or fully prevented alcohol-induced increases in proinflammatory cytokines at the mRNA level, and inhibited SYK activation. We demonstrated that TREM-1 blockade results in reduced macrophage and neutrophil infiltration and activation indicated by reduced F4/80, CD68, Ly6G, and MPO expression in the liver. These findings complement our previous data demonstrating that TREM-1 blockade using GF9-HDL and GA/ E31-HDL suppresses macrophage infiltration of the tumor in cancer mice. (17) The TREM-1 inhibitors attenuated alcohol-induced liver steatosis. HDL and the TREM-1 inhibitors also attenuated liver injury and markers of early fibrosis in alcohol-fed mice. Interestingly, the HDL vehicle control showed similar efficiency as the inhibitory formulations at the protein level of the proinflammatory cytokines. We discovered that HDL has some protective effects on ALD at the level of ALT and lipid oxidation.