Cited by 101Liver physiology and pathologyImmune cells in cancerLiver Disease Diagnosis and Treatment

Histidine‐rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease

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Bartneck, Matthias, Fech, Viktor, Ehling, Josef, Govaere, Olivier, Warzecha, Klaudia Theresa, Hittatiya, Kanishka, Vucur, Mihael, Gautheron, Jérémie +6 more·2016·Hepatology

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.

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Crossref · 10.1002/hep.28418

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Authors
Bartneck, M., Fech, V., Ehling, J., Govaere, O., Warzecha, K. T., Hittatiya, K., Vucur, M., Gautheron, J., Luedde, T., Trautwein, C., Lammers, T., Roskams, T., Jahnen‐Dechent, W., & Tacke, F.
Affiliations
  • Universitätsklinikum Aachen (DE)
  • KU Leuven (BE)
  • University of Bonn (DE)
  • Utrecht University (NL)
  • RWTH Aachen University (DE)
Corresponding author
Tacke, Frank
Venue
Hepatology
Published
2016-02-19
Volume
63
Issue
4
Pages
1310-1324
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
OpenAlex
W2221554994
Cited by
101
References
36
Citations by year
2026: 6 · 2025: 9 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 13 · 2020: 12 · 2019: 11 · 2018: 8 · 2017: 6 · 2016: 6
FWCI
3.95
Type
journal article
Language
en
Open access
Locations
  • Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • University of Twente Research Information (publishedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
  • University of Twente Research Information (submittedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • Deutsche Forschungsgemeinschaft (TRR57, 309495, SFB‐TRR57, DFG: SFB/TRR57)
  • RWTH Aachen University
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
histidine-rich glycoprotein, hepatic macrophages, macrophage polarization, chronic liver disease, liver fibrosis, liver inflammation, angiogenesis, steatohepatitis, chronic hepatitis C, nonalcoholic steatohepatitis, alarmins, methionine-choline-deficient diet, carbon tetrachloride-induced liver injury
MeSH terms
Histidine-Rich Glycoprotein, Animals, Biopsy, Needle, Cells, Cultured, Disease Models, Animal, Fatty Liver, Hepatitis C, Humans, Immunohistochemistry, Liver Cirrhosis, Macrophage Activation, Mice, Inbred C57BL, Prognosis, Proteins, Random Allocation, Biomarkers, Risk Assessment, Mice

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