CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell contentResearch in context
Cristina Bárcena,
Gemma Aran,
Luís Perea,
Lucía Sanjurjo,
Érica Téllez,
Anna Oncins,
Helena Masnou,
Isabel Serra,
Mónica García-Gallo,
Leonor Kremer,
Margarita Sala,
Carolina Armengol,
Pau Sancho-Bru,
Maria-Rosa Sarrias
Affiliations
Cristina Bárcena
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain
Gemma Aran
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain
Luís Perea
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
Lucía Sanjurjo
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain; Network for Biomedical Research in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain
Érica Téllez
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain
Anna Oncins
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain
Helena Masnou
Gastroenterology Dept., University Hospital Germans Trias i Pujol (HUGTiP), Badalona, Spain
Isabel Serra
Gastroenterology Dept., University Hospital Germans Trias i Pujol (HUGTiP), Badalona, Spain
Mónica García-Gallo
Protein Tools Unit and Department of Immunology and Oncology, Centro Nacional de Biotecnologia (CNB-CSIC), Madrid, Spain
Leonor Kremer
Protein Tools Unit and Department of Immunology and Oncology, Centro Nacional de Biotecnologia (CNB-CSIC), Madrid, Spain
Margarita Sala
Gastroenterology Dept., University Hospital Germans Trias i Pujol (HUGTiP), Badalona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Spain
Carolina Armengol
Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Spain; Childhood Liver Oncology Group, Program of Predictive and Personalized Medicine of Cancer (PMPCC), IGTP, Spain
Pau Sancho-Bru
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Spain
Maria-Rosa Sarrias
Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol (IGTP), Badalona, Spain; Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Spain; Corresponding author at: Innate Immunity Group, Health Sciences Research Institute Germans Trias i Pujol. Ctra Can Ruti, Camí de les Escoles s/n, Edifici Muntanya, Planta 2, 08916 Badalona, Spain.
Background: Chronic hepatic inflammation leads to liver fibrosis, which may progress to cirrhosis, a condition with high morbidity. Our aim was to assess the as yet unknown role of innate immunity protein CD5L in liver fibrosis. Methods: CD5L was measured by ELISA in plasma samples from cirrhotic (n = 63) and hepatitis (n = 39) patients, and healthy controls (n = 7), by immunohistochemistry in cirrhotic tissue (n = 12), and by quantitative RT-PCR in mouse liver cell subsets isolated by cell sorting. Recombinant CD5L (rCD5L) was administered into a murine model of CCl4-induced fibrosis, and damage, fibrosis and hepatic immune cell infiltration, including the LyC6hi (pro-fibrotic)-LyC6low (pro-resolutive) monocyte ratio were determined. Moreover, rCD5L was added into primary human hepatic stellate cells to study transforming growth factor β (TGFβ) activation responses. Findings: Cirrhotic patients showed elevated plasma CD5L concentrations as compared to patients with hepatitis and healthy controls (Mann-Whitney test p < 0·0001). Moreover, plasma CD5L correlated with disease progression, FIB4 fibrosis score (r:0·25, p < 0·0001) and tissue expression (r = 0·649; p = 0·022). Accordingly, CCl4-induced damage increased CD5L levels in total liver, particularly in hepatocytes and macrophages. rCD5L administration attenuated CCl4-induced injury and fibrosis as determined by reduced serum transaminase and collagen content. Moreover, rCD5L inhibited immune cell infiltration and promoted a phenotypic shift in monocytes from LyC6hi to LyC6low. Interestingly, rCD5L also had a direct effect on primary human hepatic stellate cells promoting SMAD7 expression, thus repressing TGFβ signalling. Interpretation: Our study identifies CD5L as a key pleiotropic inhibitor of chronic liver injury. Fund: Fundació Marató TV3, AGAUR and the ISCIII-EDRF. Keywords: Macrophage, Apoptosis inhibitor of macrophages, TGFB, Hepatic stellate cells, SMAD7
