Histidine‐rich glycoprotein promotes macrophage activation and inflammation in chronic liver disease
Open accessAbstract
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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HRG-deficient mice developed less fibrosis and showed reduced macrophage infiltration, accompanied by a shift toward a restorative phenotype, likely promoting pro-angiogenic and tissue-reparative responses.
“HRG-deficient mice developed less fibrosis and showed reduced macrophage infiltration, accompanied by a shift toward a restorative phenotype, likely promoting pro-angiogenic and tissue-reparative responses.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [89]
These HRG findings were further validated in a MASH model.
“These findings were further validated in a MASH model.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [89]
HRG is upregulated in cirrhotic MASH and HCV patients, as well as in CCl4 and MASH mouse models.
“Bartneck et al. (89) reported that histidine-rich glycoprotein (HRG), a hepatocyte-derived plasma protein, is upregulated in cirrhotic MASH and hepatitis C virus (HCV) patients, as well as in CCl4 and MASH mouse models.”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [89]
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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
- ORCID
- 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
- bronze
- doi.org
- 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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