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

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TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation
Journal of Hepatology ( IF 26.8 ) Pub Date : 2022-06-22 , DOI: 10.1016/j.jhep.2022.05.044
Ibone Labiano ₁ , Aloña Agirre-Lizaso ₁ , Paula Olaizola ₁ , Anne Echebarria ₁ , Maider Huici-Izagirre ₁ , Irene Olaizola ₁ , Aitor Esparza-Baquer ₁ , Omar Sharif ₂ , Elizabeth Hijona ₃ , Piotr Milkiewicz ₄ , Malgorzata Milkiewicz ₅ , Francisco González-Romero ₆ , Patricia Aspichueta ₇ , Maria J Monte ₈ , Jose J G Marin ₈ , Mihael Vucur ₉ , Tom Luedde ₉ , Marco Marzioni ₁₀ , Derek A Mann ₁₁ , Luis Bujanda ₁₂ , Pedro M Rodrigues ₁₃ , Jesus M Banales ₁₄ , Maria J Perugorria ₁₅

Affiliation

Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain.
Institute 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.
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 Nursing, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Donostia-San Sebastian, Spain.
Liver 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.
Department of Medical Biology, Pomeranian Medical University in Szczecin, Szczecin, Poland.
Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Leioa, Spain.
CIBERehd, 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.
CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, IBSAL, Salamanca, Spain.
Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty, Heinrich Heine University, 40225 Duesseldorf, Germany.
Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ancona, Italy.
Institute 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.
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 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 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.
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.

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.

中文翻译：

TREM-2 通过充当炎症的负调节因子，在胆汁淤积中发挥保护作用

背景与目标

炎症，特别是由细菌成分从肠道转移到肝脏并与 Toll 样受体 (TLR) 结合介导的炎症，是胆汁淤积性肝损伤的核心。骨髓细胞 2 (TREM-2) 上表达的触发受体可抑制 TLR 介导的信号传导，并在肝细胞损伤和癌变中发挥保护作用。本研究旨在评估 TREM-2 在胆汁淤积中的作用。

方法

对原发性胆汁性胆管炎 (PBC) 或原发性硬化性胆管炎 (PSC) 患者的肝脏以及胆汁淤积小鼠模型中的TREM-2表达进行了分析。对野生型 (WT) 和Trem-2缺陷型 ( Trem-2 ^-/- ) 小鼠进行实验性胆汁淤积和肠道绝育。将原代培养的库普弗细胞与脂多糖和/或熊去氧胆酸（UDCA）一起孵育，并分析炎症反应。

结果

TREM-2表达在 PBC 或 PSC 患者的肝脏以及胆汁淤积小鼠模型中上调。与WT相比， Trem-2 ^-/-小鼠对胆管结扎（BDL）诱导的阻塞性胆汁淤积或α-异硫氰酸萘酯（ANIT）诱导的胆汁淤积的反应加剧。其特征是坏死性细胞死亡、炎症反应和胆道扩张增强。抗生素治疗部分消除了 BDL 后Trem-2 ^-/-小鼠中观察到的效果。 WT 小鼠肝脏中 TREM-2 的实验性过度表达下调了 ANIT 诱导的 IL-33 表达和中性粒细胞募集。 UDCA 调节原代培养的小鼠 Kupffer 细胞中Trem-1和Trem-2 的表达，并通过 TREM-2 依赖性机制抑制炎症基因转录。

结论

TREM-2 在胆汁淤积期间充当炎症的负调节因子，代表了一个新的潜在治疗靶点。

外行总结

胆汁淤积（胆汁流动减少或停止）会导致肝损伤。当肠道来源的细菌成分与肝脏驻留免疫细胞上的受体（特别是 Toll 样受体或 TLR）相互作用时，这种损伤会加剧，从而促进炎症。在此，我们证明抗炎受体 TREM-2 抑制 TLR 介导的信号传导，从而防止胆汁淤积引起的肝损伤。因此，TREM-2可能是胆汁淤积的潜在治疗靶点。

更新日期：2022-06-22

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