title: Stabilin-1 expression defines a subset of macrophages that mediate tissue homeostasis and prevent fibrosis in chronic liver injury.
abstract: Macrophages are key regulators of fibrosis development and resolution. Elucidating the mechanisms by which they mediate this process is crucial for establishing their therapeutic potential. Here, we use experimental models of liver fibrosis to show that deficiency of the scavenger receptor, stabilin-1, exacerbates fibrosis and delays resolution during the recovery phase. We detected a subset of stabilin-1(+) macrophages that were induced at sites of cellular injury close to the hepatic scar in mouse models of liver fibrosis and in human liver disease. Stabilin-1 deficiency abrogated malondialdehyde-LDL (MDA-LDL) uptake by hepatic macrophages and was associated with excess collagen III deposition. Mechanistically, the lack of stabilin-1 led to elevated intrahepatic levels of the profibrogenic chemokine CCL3 and an increase in GFAP(+) fibrogenic cells. Stabilin-1(-/-) macrophages demonstrated a proinflammatory phenotype during liver injury and the normal induction of Ly6C(lo) monocytes during resolution was absent in stabilin-1 knockouts leading to persistence of fibrosis. Human stabilin-1(+) monocytes efficiently internalized MDA-LDL and this suppressed their ability to secrete CCL3, suggesting that loss of stabilin-1 removes a brake to CCL3 secretion. Experiments with cell-lineage-specific knockouts revealed that stabilin-1 expression in myeloid cells is required for the induction of this subset of macrophages and that increased fibrosis occurs in their absence. This study demonstrates a previously unidentified regulatory pathway in fibrogenesis in which a macrophage scavenger receptor protects against organ fibrosis by removing fibrogenic products of lipid peroxidation. Thus, stabilin-1(+) macrophages shape the tissue microenvironment during liver injury and healing.
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520, Turku, Finland;
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Patten
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520, Turku, Finland;
authors.forename: Joona
authors.initials: J
authors.lastname: Valtonen
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520, Turku, Finland;
authors.forename: Marika
authors.initials: M
authors.lastname: Karikoski
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520, Turku, Finland;
authors.forename: Heidi
authors.initials: H
authors.lastname: Gerke
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Harriet
authors.initials: H
authors.lastname: Dawes
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520, Turku, Finland;
authors.forename: Juha
authors.initials: J
authors.lastname: Laurila
authors.affiliation: Proteomics Core Facility, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, University of Oulu, FI-90014, Oulu, Finland;
authors.forename: Steffen
authors.initials: S
authors.lastname: Ohlmeier
authors.affiliation: MediCity Research Laboratory, Department of Medical Biochemistry and Genetics, University of Turku, FI-20520, Turku, Finland;
authors.forename: Kati
authors.initials: K
authors.lastname: Elima
authors.affiliation: School of Cancer Sciences, University of Birmingham B15 2TT, Birmingham, United Kingdom.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Hübscher
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: Chris J
authors.identifier: 0000-0002-9651-1264
authors.initials: CJ
authors.lastname: Weston
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520, Turku, Finland;
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom;
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.affiliation: MediCity Research Laboratory and Department of Medical Microbiology and Immunology, University of Turku, FI-20520, Turku, Finland;
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.affiliation: National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, United Kingdom; s.shetty@bham.ac.uk.
authors.forename: Shishir
authors.initials: S
authors.lastname: Shetty
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications*; D054405:Chemokine CCL3 / Q000502:physiology; D002796:Choline Deficiency / Q000150:complications; D006706:Homeostasis; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008103:Liver Cirrhosis / Q000517:prevention & control*; D008264:Macrophages / Q000502:physiology*; D008315:Malondialdehyde / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D054405:Chemokine CCL3; D008077:Lipoproteins, LDL; C486732:Stab1 protein, mouse; C502964:malondialdehyde-low density lipoprotein, mouse; D008315:Malondialdehyde; D002251:Carbon Tetrachloride
keywords: CCL3; fibrosis; liver; macrophages; stabilin-1