1. TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation
- Author
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Enfermería II, Fisiología, Medicina, Erizaintza II, Fisiologia, Medikuntza, Labiano Ciriza, Ibone, Agirre Lizaso, Aloña, Olaizola Rebe, Paula, Echebarria, Anne, Huici Izagirre, Maider, Olaizola, Irene, Esparza Baquer, Aitor, Sharif, Omar, Hijona Muruamendiaraz, Elizabeth, Milkiewicz, Piotr, Milkiewicz, Malgorzata, González Romero, Francisco, Aspichueta Celaá, Patricia, Monte, María J., García Marín, Jose Juan, Vucur, Michael, Luedde, Tom, Marzioni, Marco, Mann, Derek A., Bujanda Fernández de Pierola, Luis, Perugorria Montiel, María Jesús, Enfermería II, Fisiología, Medicina, Erizaintza II, Fisiologia, Medikuntza, Labiano Ciriza, Ibone, Agirre Lizaso, Aloña, Olaizola Rebe, Paula, Echebarria, Anne, Huici Izagirre, Maider, Olaizola, Irene, Esparza Baquer, Aitor, Sharif, Omar, Hijona Muruamendiaraz, Elizabeth, Milkiewicz, Piotr, Milkiewicz, Malgorzata, González Romero, Francisco, Aspichueta Celaá, Patricia, Monte, María J., García Marín, Jose Juan, Vucur, Michael, Luedde, Tom, Marzioni, Marco, Mann, Derek A., Bujanda Fernández de Pierola, Luis, and Perugorria Montiel, María Jesús
- Abstract
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
- Published
- 2022