Vucur, M. (Mihael)

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    TREM-2 Plays a Protective Role in Cholestasis By Acting as a Negative Regulator of Inflammation
    (2022) Marzioni, M. (Marco); Vucur, M. (Mihael); Echebarria, A. (Anne); Sharif, O. (Omar); Rodrigues, P.M. (Pedro M.); Bañales-Asurmendi, J.M. (Jesus Maria); Luedde, T. (Tom); Perugorria, M.J. (María J.); Monte, M.J. (María J.); Mann, D.A. (Derek A.); Bujanda, L. (Luis); Hijona, E. (Elizabeth); Milkiewicz, P. (Piotr); Olaizola, P. (Paula); Olaizola, I. (Irene); Labiano, I. (Ibone); Huici-Izagirre, M. (Maider); Agirre-Lizaso, A. (Aloña); Aspichueta, P. (Patricia); Marin, J.J.G (Jose J.G.); González-Romero, F. (Francisco); Esparza-Baquer, A. (Aitor)
    Background & 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 (spe-cifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.