J Hepatol
Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain; CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain. Electronic address:
Published: October 2022
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.
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http://dx.doi.org/10.1016/j.jhep.2022.05.044 | DOI Listing |
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