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

Lookup NU author(s): Professor Derek Mann



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2022 The Author(s). 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 patients with primary biliary cholangitis (PBC) or primary sclerosing 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. Primary cultured Kupffer cells were incubated with lipopolysaccharide 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, inflammatory responses and biliary expansion. Antibiotic treatment 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 dampened inflammatory gene transcription via a TREM-2-dependent mechanism. Conclusions: TREM-2 acts as a negative regulator of inflammation during cholestasis, representing a novel potential therapeutic 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 (specifically 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.

Publication metadata

Author(s): Labiano I, Agirre-Lizaso A, Olaizola P, Echebarria A, Huici-Izagirre M, Olaizola I, Esparza-Baquer A, Sharif O, Hijona E, Milkiewicz P, Milkiewicz M, Gonzalez-Romero F, Aspichueta P, Monte MJ, Marin JJG, Vucur M, Luedde T, Marzioni M, Mann DA, Bujanda L, Rodrigues PM, Banales JM, Perugorria MJ

Publication type: Article

Publication status: Published

Journal: Journal of Hepatology

Year: 2022

Volume: 77

Issue: 4

Pages: 991-1004

Print publication date: 01/10/2022

Online publication date: 22/06/2022

Acceptance date: 22/05/2022

Date deposited: 29/06/2023

ISSN (print): 0168-8278

ISSN (electronic): 1600-0641

Publisher: Elsevier BV


DOI: 10.1016/j.jhep.2022.05.044

PubMed id: 35750136


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