TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation

Backgroundand aims: inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis.Methods: TREM-2 expression was analyzed in the livers of pa-tients with primary biliary cholangitis (PBC) or primary scle-rosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Pri-mary cultured Kupffer cells were incubated with lipopolysac-charide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed.Results: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/-mice. This was characterized by enhanced necroptotic cell death, in-flammatory responses and biliary expansion. Antibiotic treat-ment partially abrogated the effects observed in Trem-2-/-mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and damp-ened inflammatory gene transcription via a TREM-2-dependent mechanism.Conclusions: TREM-2 acts as a negative regulator of inflamma-tion during cholestasis, representing a novel potential thera-peutic target.Lay summary: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors
European Union (EU); Horizon 2020; European Research Council (ERC); Spanish Carlos III Health Institute (ISCIII); Fondo Europeo de Desarrollo Regional (FEDER); Diputación Foral de Gipuzkoa; Department of Health of the Basque Country; Euskadi RIS3; Department of Industry of the Basque Country; Junta de Castilla y Leon; La Caixa Scientific Foundation; Centro Internacional sobre el Envejecimiento; Fundació Marato TV3; Austrian Science Fund; German Research Foundation (DFG); German Ministry of Health (BMG); DEEP LIVER; Università Politecnica delle Marche; CRUK; MRC; Spanish Ministry of Economy and Competitiveness; MINECO; “Ramón y Cajal” Programme; Ministry of Universities ; University of the Basque Country; Instituto de Salud Carlos III (CIBERehd); Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation); SFB-CRC 1382-Project A01