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Abstract Details
TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation
J Hepatol. 2022 Oct;77(4):991-1004. doi: 10.1016/j.jhep.2022.05.044. Epub 2022 Jun 22.
1Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain.
2Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria; Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria.
3Department 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 Nursing, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Donostia-San Sebastian, Spain.
4Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery of the Medical University of Warsaw, Warsaw, Poland; Translational Medicine Group, Pomeranian Medical University in Szczecin, Szczecin, Poland.
5Department of Medical Biology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
6Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain.
7CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain; Biocruces Health Research Institute, Barakaldo, Spain.
8CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.
9Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine University, 40225 Duesseldorf, Germany.
10Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy.
11Institute of Cellular Medicine, Faculty of Medical Sciences, 4th Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK; Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey; Fibrofind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, UK.
12Department 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.
13Department 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; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
14Department 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; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain. Electronic address: jesus.banales@biodonostia.org.
15Department 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: matxus.perugorria@biodonostia.org.
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 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.
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