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

By inducing TNF-α, IL-6, MCP-1, IL-8, and granulocyte-macrophage colony-stimulating factor and inhibiting IL-10 production, TREM-1 is involved in activation and recruitment of monocytes and modulation of inflammatory responses. (40) Furthermore, TREM-1 expression was highly up-regulated on the surface of infiltrating monocytes and neutrophils in human tissues infected by bacteria, highlighting the importance of this receptor in these processes. (7) In alcoholic hepatitis, neutrophils infiltrate the liver, inducing oxidative stress and cytotoxicity that contributes to the high mortality of the disease. (2) We showed that these processes can be attenuated by TREM-1 inhibitors. Mechanistically, the GF9-HDL and GA/E31-HDL formulations target the liver more efficiently than only the peptides alone and release the TREM-1 inhibitory sequences inside the target cells where these peptides likely inhibit TREM-1 signaling by disrupting the intramembrane interactions of the TREM-1 receptor and its signaling adaptor molecule DNAX activation protein of 12kDa [Correction made 31 October, 2018. The correct protein was noted.] (Fig. 7) . (15) (16) (17) We previously hypothesized that the observed preferential endocytosis of GF9-HDL and GA/E31-HDL by macrophages and hepatic clearance of these complexes are mediated by SR recognition of putative epitopes in the modified apo A-I peptide constituents of GF9-HDL and GA/E31-HDL. (16, 17, 19) Our current findings indicate that GF9-HDL and GA/E31-HDL are largely recognized by SR-A on macrophages (Fig. 7) . We also observed SR-BI-mediated uptake, which likely explains the previously observed hepatic clearance for these complexes in another animal model. (19) While these data confirm our hypothesis, future studies are needed to determine the clearance properties for GF9-HDL and GA/E31-HDL in ALD.