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

endoplasmic reticulum stress and trigger release of damage-associated molecular patterns (DAMPs). In addition, excessive and/or chronic alcohol consumption disrupts the gut barrier function and changes the gut microbiome, leading to increased levels of microbial pathogen-associated molecular patterns (PAMPs) in the circulation. PAMPs from portal circulation and locally released DAMPs provide proinflammatory signals in the liver for activation of resident Kupffer cells and recruitment of activated macrophages and neutrophil leukocytes from the bone marrow. (1, 2) Increased lipopolysaccharide (LPS) levels in animal models of ALD and in patients with alcoholic hepatitis contribute to macrophage and neutrophil activation and proinflammatory cascade activation by theTLR4 receptor complex. Cytokines induced by PAMPs and DAMPs contribute to a self-perpetuating proinflammatory state that characterizes alcoholic hepatitis. (3) TREM-1 is an activating receptor complex that is expressed on neutrophils and monocytes/macrophages and amplifies TLR signaling. (4) It has been shown that TREM-1 can amplify TLR4-mediated as well as TLR2-mediated proinflammatory signals. (5, 6) The expression and function of TREM-1 has been indicated in various inflammatory diseases, including sepsis, cancer, retinopathy of prematurity (ROP), atherosclerosis, and experimental colitis. (7) (8) (9) Expression of TREM-1 in hepatic stellate cells was proposed as a prognostic factor in hepatitis B-related hepatocellular carcinoma (HCC), and TREM-1-mediated Kupffer cell activation was found in HCC. (10, 11) Little is known about the role of TREM-1 in ALD. Here, we hypothesized that inhibition of TREM-1 will ameliorate inflammation and liver damage in ALD, given the known role of TREM-1 in myeloid cell activation and amplification of proinflammatory signaling.