title: Histidine-rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease.
abstract: Pathogen- and injury-related danger signals as well as cytokines released by immune cells influence the functional differentiation of macrophages in chronic inflammation. Recently, the liver-derived plasma protein, histidine-rich glycoprotein (HRG), was demonstrated, in mouse tumor models, to mediate the transition of alternatively activated (M2) to proinflammatory (M1) macrophages, which limit tumor growth and metastasis. We hypothesized that liver-derived HRG is a critical endogenous modulator of hepatic macrophage functionality and investigated its implications for liver inflammation and fibrosis by comparing C57BL/6N wild-type (WT) and Hrg(-/-) mice. In homeostatic conditions, hepatic macrophages were overall reduced and preferentially polarized toward the anti-inflammatory M2 subtype in Hrg(-/-) mice. Upon chronic liver damage induced by CCl4 or methionine-choline-deficient (MCD) diet, liver injury and fibrosis were attenuated in Hrg(-/-) , compared to WT, mice. Macrophage populations were reduced and skewed toward M2 polarization in injured livers of Hrg(-/-) mice. Moreover, HRG-deficient mice showed significantly enhanced hepatic vascularization by micro-computed tomography and histology, corroborating proangiogenic activities of M2-polarized liver macrophages. Purified HRG protein induced, but HRG-deficient serum prevented, M1 macrophage differentiation in vitro. Accordingly, Hrg(-/-) mice transplanted with Hrg(+/+) bone marrow, but not Hrg(-/-) -transplanted Hrg(+/+) mice, remained protected from experimental steatohepatitis. Consistent with these findings, patients with chronic hepatitis C and nonalcoholic steatohepatitis significantly up-regulated hepatocytic HRG expression, which was associated with M1 polarization of adjacent macrophages.
  
  
  CONCLUSIONS
  Liver-derived HRG, similar to alarmins, appears to be an endogenous molecular factor promoting polarization of hepatic macrophages toward the M1 phenotype, thereby promoting chronic liver injury and fibrosis progression, but limiting angiogenesis. Therefore, controlling tissue levels of HRG or PGF might be a promising strategy in chronic inflammatory liver diseases.
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bartneck
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Fech
authors.affiliation: Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Ehling
authors.affiliation: Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, KU Leuven, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Govaere
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Klaudia Theresa
authors.initials: KT
authors.lastname: Warzecha
authors.affiliation: Institute of Pathology, University Bonn, Bonn, Germany.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Hittatiya
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Mihael
authors.initials: M
authors.lastname: Vucur
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Gautheron
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.|Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.|Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Twan
authors.initials: T
authors.lastname: Lammers
authors.affiliation: Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, KU Leuven, Belgium.
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.affiliation: Helmholtz-Institute for Biomedical Engineering, Biointerface Laboratory, RWTH Aachen, Germany.
authors.forename: Willi
authors.initials: W
authors.lastname: Jahnen-Dechent
authors.affiliation: Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001707:Biopsy, Needle; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000473:pathology* / Q000503:physiopathology; D006526:Hepatitis C / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000473:pathology* / Q000503:physiopathology; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D011379:Prognosis; D011506:Proteins / Q000378:metabolism*; D011897:Random Allocation; D018570:Risk Assessment; D000099053:Histidine-Rich Glycoprotein
chemical_list: D015415:Biomarkers; D011506:Proteins; D000099053:Histidine-Rich Glycoprotein