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

While the ligand of TREM-1 is still unknown, it has been shown that TREM-1 activation amplifies inflammation and synergizes with TLR signaling pathways. (34) It was also observed that bacterial infection and challenge with LPS or lipoteichoic acid increase TREM-1 expression, (7) indicating a positive feedback loop among PAMP exposure, TREM-1 expression, and inflammatory cytokine induction. Different DAMPs, such as high-mobility group box protein 1 [Correction made 31 October, 2018. The correct protein was noted.] and heat shock protein 70, have been suggested to stimulate TREM-1, (35) while other studies found cell (granulocyte and platelet)-surfaceassociated activators as well. (35, 36) Both PAMPs and DAMPs are present in ALD, providing potential mechanisms for TREM-1 up-regulation in this disease. Alcohol induces changes in the gut microbiome and disrupts the gut barrier function, resulting in increased levels of endotoxin and microbial PAMPs in circulation. (1, 37) Alcohol also causes hepatocyte damage that leads to the release of DAMPs, (23) and all these processes contribute to TREM-1 activation. TREM-1 signaling leads to phosphorylation and activation of SYK, which has been indicated as a major regulator in inflammatory processes in ALD. (38) TREM-1 also amplifies TLR4 signaling that involves downstream SYK activation and phosphorylation. (38) Indeed, we found increased total and phosphorylated SYK levels in the livers of alcohol-fed mice that was attenuated by TREM-1 inhibitor administration. A previous study showed that inhibition of SYK activation attenuates alcohol-induced liver inflammation, cell death, and steatosis, suggesting that the SYK pathway could be a feasible therapeutic target in ALD. (24) SYK is expressed in a wild spectrum of cells, while TREM-1 inhibition may specifically modulate macrophages, neutrophils, and stellate cells that each play a role in ALD. Another advantage of TREM-1 inhibition is that it likely attenuates signaling from a broader spectrum of TLRs, not only TLR4.