Matthias Bartneck1, Viktor Fech1, Josef Ehling2, Olivier Govaere3, Klaudia Theresa Warzecha1, Kanishka Hittatiya4, Mihael Vucur1, Jérémie Gautheron1, Tom Luedde1, Christian Trautwein1, Twan Lammers2,5,6, Tania Roskams3, Willi Jahnen-Dechent7, Frank Tacke1. 1. Department of Medicine III, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany. 2. Department of Experimental Molecular Imaging, Helmholtz Institute for Biomedical Engineering, RWTH University-Hospital Aachen, Aachen, Germany. 3. Translational Cell & Tissue Research Unit, Department of Imaging & Pathology, KU Leuven, Belgium. 4. Institute of Pathology, University Bonn, Bonn, Germany. 5. Department of Targeted Therapeutics, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands. 6. Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. 7. Helmholtz-Institute for Biomedical Engineering, Biointerface Laboratory, RWTH Aachen, Germany.
Abstract
UNLABELLED: 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.
UNLABELLED: 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 mousetumor 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-deficientmice 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: Charles P Najt; Subramanian Senthivinayagam; Mohammad B Aljazi; Kelly A Fader; Sandra D Olenic; Julienne R L Brock; Todd A Lydic; A Daniel Jones; Barbara P Atshaves Journal: Am J Physiol Gastrointest Liver Physiol Date: 2016-03-11 Impact factor: 4.052
Authors: Tobias Puengel; Sander Lefere; Jana Hundertmark; Marlene Kohlhepp; Christian Penners; Frederique Van de Velde; Bruno Lapauw; Anne Hoorens; Lindsey Devisscher; Anja Geerts; Stephanie Boehm; Qihong Zhao; John Krupinski; Edgar D Charles; Bradley Zinker; Frank Tacke Journal: Int J Mol Sci Date: 2022-06-15 Impact factor: 6.208
Authors: Detlef Schuppan; Henning Grønbæk; Konstantin Kazankov; Simon Mark Dahl Jørgensen; Karen Louise Thomsen; Holger Jon Møller; Hendrik Vilstrup; Jacob George Journal: Nat Rev Gastroenterol Hepatol Date: 2019-03 Impact factor: 46.802
Authors: Guido Carpino; Valerio Nobili; Anastasia Renzi; Cristiano De Stefanis; Laura Stronati; Antonio Franchitto; Anna Alisi; Paolo Onori; Rita De Vito; Gianfranco Alpini; Eugenio Gaudio Journal: PLoS One Date: 2016-06-16 Impact factor: 3.240