dc.contributor.author | Labiano Ciriza, Ibone | |
dc.contributor.author | Agirre Lizaso, Aloña | |
dc.contributor.author | Olaizola Rebe, Paula | |
dc.contributor.author | Echebarria, Anne | |
dc.contributor.author | Huici Izagirre, Maider | |
dc.contributor.author | Olaizola, Irene | |
dc.contributor.author | Esparza Baquer, Aitor | |
dc.contributor.author | Sharif, Omar | |
dc.contributor.author | Hijona Muruamendiaraz, Elizabeth | |
dc.contributor.author | Milkiewicz, Piotr | |
dc.contributor.author | Milkiewicz, Malgorzata | |
dc.contributor.author | González Romero, Francisco | |
dc.contributor.author | Aspichueta Celaá, Patricia | |
dc.contributor.author | Monte, María J. | |
dc.contributor.author | García Marín, Jose Juan | |
dc.contributor.author | Vucur, Michael | |
dc.contributor.author | Luedde, Tom | |
dc.contributor.author | Marzioni, Marco | |
dc.contributor.author | Mann, Derek A. | |
dc.contributor.author | Bujanda Fernández de Pierola, Luis | |
dc.contributor.author | Perugorria Montiel, María Jesús | |
dc.date.accessioned | 2022-12-15T16:16:56Z | |
dc.date.available | 2022-12-15T16:16:56Z | |
dc.date.issued | 2022-10 | |
dc.identifier.citation | Journal of Hepatology 77(4) : 991-1004 (2022) | es_ES |
dc.identifier.issn | 0168-8278 | |
dc.identifier.issn | 1600-0641 | |
dc.identifier.uri | http://hdl.handle.net/10810/58844 | |
dc.description.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 (spe-cifically 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. | es_ES |
dc.description.sponsorship | Spanish Carlos III Health Institute (ISCIII) [J.M. Banales (FIS PI18/01075, PI21/00922 and Miguel Servet Program CPII19/00008); M.J. Perugorria (FIS PI14/00399, PI17/00022 and PI20/00186); J.J.G. Marin (FIS PI16/00598 and PI19/00819); P.M. Rodrigues (Sara Borrell CD19/00254)] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); “Instituto de Salud Carlos III” [CIBERehd: M.J. Monte, J.J.G. Marin, J.M. Banales, M.J. Perugorria, P. Aspichueta, P.M. Rodrigues and L. Bujanda], Spain; “Diputación Foral de Gipuzkoa” (M.J. Perugorria: DFG18/114), Department of Health of the Basque Country (M.J. Perugorria: 2019111024, 2015111100 and J.M. Banales: 2021111021), “Euskadi RIS3” (J.M. Banales: 2019222054, 2020333010, 2021333003), and Department of Industry of the Basque Country (J.M. Banales: Elkartek: KK-2020/00008); “Junta de Castilla y Leon” (J.J.G. Marin: SA063P17). La Caixa Scientific Foundation (J.M. Banales: HR17-00601). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); “Centro Internacional sobre el Envejecimiento” (J.J.G. Marin: OLD-HEPAMARKER, 0348_CIE_6_E); Fundació Marato TV3 (J.J.G. Marin: Ref. 201916-31). O Sharif was funded by the Austrian Science Fund (FWF-P35168). Work in the lab of T. Luedde was funded by the European Research Council (ERC) (Grant Agreement 771083), the German Research Foundation (DFG – LU 1360/3-2 (279874820), LU 1360/4-(1461704932) and SFB-CRC 1382-Project A01) and the German Ministry of Health (BMG – DEEP LIVER 2520DAT111). Contributions of M. Marzioni were funded by the Università Politecnica delle Marche PSA2017_UNIVPM grant. Contributions of DAM were supported by programme grants from CRUK (C18342/A23390) and MRC (MR/K0019494/1 and MR/R023026/1). MJ Perugorria was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Programme RYC-2015-17755), I. Labiano, A. Agirre-Lizaso, P. Olaizola, A. Echebarria and F. González-Romero by the Basque Government (PRE_2016_1_0152, PRE_2018_1_0184, PRE_2016_1_0269 PRE_2020_1_0080, PRE_2018_1_0120, respectively), I. Olaizola by the Ministry of Universities (FPU 19/03327) and A. Esparza-Baquer by the University of the Basque Country (PIF2014/11). The funding sources had no involvement in study design, data collection and analysis, decision to publish, or preparation of the article. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Elsevier | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/ERC/771083 | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/RYC-2015-17755 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/es/ | * |
dc.subject | TREM receptors | es_ES |
dc.subject | cholangiopathies | es_ES |
dc.subject | inflammation | es_ES |
dc.subject | ursodeoxycholic acid | es_ES |
dc.subject | innate immunity | es_ES |
dc.subject | liver resident macrophages | es_ES |
dc.title | TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | © 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) | es_ES |
dc.rights.holder | Atribución-NoComercial-SinDerivadas 3.0 España | * |
dc.relation.publisherversion | https://www.sciencedirect.com/science/article/pii/S0168827822003725?via%3Dihub | es_ES |
dc.identifier.doi | 10.1016/j.jhep.2022.05.044 | |
dc.contributor.funder | European Commission | |
dc.departamentoes | Enfermería II | es_ES |
dc.departamentoes | Fisiología | es_ES |
dc.departamentoes | Medicina | es_ES |
dc.departamentoeu | Erizaintza II | es_ES |
dc.departamentoeu | Fisiologia | es_ES |
dc.departamentoeu | Medikuntza | es_ES |