title: TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency.
abstract: Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis. Cirrhotic patients show low expression of GNMT that is absent in hepatocellular carcinoma (HCC) samples. Accordingly, GNMT deficiency in mice leads to steatohepatitis, fibrosis, cirrhosis, and HCC. Lack of GNMT triggers NK cell activation in GNMT(-/-) mice and depletion of TRAIL significantly attenuates acute liver injury and inflammation in these animals. Chronic inflammation leads to fibrogenesis, further contributing to the progression of chronic liver injury regardless of the etiology. The aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis. For this we generated double TRAIL(-/-)/GNMT(-/-) mice in which we found that TRAIL deficiency efficiently protected the liver against chronic liver injury and fibrogenesis in the context of GNMT deficiency. Next, to better delineate the implication of TRAIL-producing NK cells during fibrogenesis we performed bile duct ligation (BDL) to GNMT(-/-) and TRAIL(-/-)/GNMT(-/-) mice. In GNMT(-/-) mice, exacerbated fibrogenic response after BDL concurred with NK1.1(+) cell activation. Importantly, specific inhibition of TRAIL-producing NK cells efficiently protected GNMT(-/-) mice from BDL-induced liver injury and fibrogenesis. Finally, TRAIL(-/-)/GNMT(-/-) mice showed significantly less fibrosis after BDL than GNMT(-/-) mice further underlining the relevance of the TRAIL/DR5 axis in mediating liver injury and fibrogenesis in GNMT(-/-) mice. Finally, in vivo silencing of DR5 efficiently protected GNMT(-/-) mice from BDL-liver injury and fibrogenesis, overall underscoring the key role of the TRAIL/DR5 axis in promoting fibrogenesis in the context of absence of GNMT. Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease.
authors.affiliation: Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Fernández-Álvarez
authors.affiliation: Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Gutiérrez-de Juan
authors.affiliation: Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.
authors.forename: Imanol
authors.initials: I
authors.lastname: Zubiete-Franco
authors.affiliation: Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.
authors.forename: Lucia
authors.initials: L
authors.lastname: Barbier-Torres
authors.affiliation: Unidad de Hepatología, Instituto de Investigación Sanitaria La Fé, Valencia, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Lahoz
authors.affiliation: Liver Unit, Hospital Clínic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Parés
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Zigmund
authors.initials: Z
authors.lastname: Luka
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Conrad
authors.initials: C
authors.lastname: Wagner
authors.affiliation: Division of Gastrointestinal and Liver Diseases, USC Research Center for Liver Diseases, Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.affiliation: Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.affiliation: 1] Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain [2] Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Martínez-Chantar
authors.affiliation: 1] Department of Metabolomics, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Derio, Spain [2] Ikerbasque, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Naiara
authors.initials: N
authors.lastname: Beraza
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000276:immunology*; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D015153:Blotting, Western; D058625:End Stage Liver Disease / Q000209:etiology* / Q000473:pathology*; D005434:Flow Cytometry; D050938:Glycine N-Methyltransferase / Q000172:deficiency* / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000378:metabolism*; D008026:Ligation; D051379:Mice; D018345:Mice, Knockout; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D050938:Glycine N-Methyltransferase