CXCL4 Downregulates the Atheroprotective Hemoglobin Receptor CD163 in Human Macrophages
Open accessAbstract
Rationale : CXCL4 is a platelet-derived chemokine that promotes macrophage differentiation from monocytes. Deletion of the PF4 gene that encodes CXCL4 reduces atherosclerotic lesions in ApoE −/− mice. Objective : We sought to study effects of CXCL4 on macrophage differentiation with possible relevance for atherogenesis. Methods and Results : Flow cytometry for expression of surface markers in macrophage colony–stimulating factor (M-CSF)– and CXCL4-induced macrophages demonstrated virtually complete absence of the hemoglobin scavenger receptor CD163 in CXCL4-induced macrophages. mRNA for CD163 was downregulated as early as 2 hours after CXCL4. CD163 protein reached a minimum after 3 days, which was not reversed by treatment of cells with M-CSF. The CXCL4 effect was entirely neutralized by heparin, which bound CXCL4 and prevented CXCL4 surface binding to monocytes. Pretreatment of cells with chlorate, which inhibits glycosaminoglycan synthesis, strongly inhibited CXCL4-dependent downregulation of CD163. Similar to recombinant CXCL4, releasate from human platelets also reduced CD163 expression. CXCL4-differentiated macrophages were unable to upregulate the atheroprotective enzyme heme oxygenase-1 at the RNA and protein level in response to hemoglobin–haptoglobin complexes. Immunofluorescence of human atherosclerotic plaques demonstrated presence of both CD68 + CD163 + and CD68 + CD163 − macrophages. PF4 and CD163 gene expression within human atherosclerotic lesions were inversely correlated, supporting the in vivo relevance of CXCL4-induced downregulation of CD163. Conclusions : CXCL4 may promote atherogenesis by suppressing CD163 in macrophages, which are then unable to upregulate the atheroprotective enzyme heme oxygenase-1 in response to hemoglobin.
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A hybrid macrophage phenotype showing some M2 and M1 features is induced by CXCL4 released by platelets at the inception of the injury response.
“In addition, a hybrid macrophage phenotype has been recently identified that shows some M2 as well as M1 features and is induced by CXCL4 (platelet factor 4) released by platelets at the inception of the injury response.98”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [98]
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“In addition, a hybrid macrophage phenotype has been recently identified that shows some M2 as well as M1 features and is induced by CXCL4 (platelet factor 4) released by platelets at the inception of the injury response.(98) The in vivo relevance of CX3CL1 and its receptor (CX3CR1) for the wound healing response is su…”
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- Authors
- Gleissner, C. A., Shaked, I., Erbel, C., Böckler, D., Katus, H. A., & Ley, K.
- Affiliations
- La Jolla Institute for Immunology (US)
- From the Division of Inflammation Biology (C.A.G., I.S., K.L.), La Jolla Institute for Allergy & Immunology, Calif; and Departments of Cardiology (C.A.G., C.E., H.A.K.) and Vascular Surgery (D.B.), University of Heidelberg, Germany.
- Venue
- Circulation Research
- Published
- 2010-01-08
- Volume
- 106
- Issue
- 1
- Pages
- 203-211
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2876722
- OpenAlex
- W2164138396
- Cited by
- 165
- References
- 45
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 10 · 2023: 14 · 2022: 16 · 2021: 3 · 2020: 8 · 2019: 8 · 2018: 8 · 2017: 11 · 2016: 8 · 2015: 14 · 2014: 16 · 2013: 12 · 2012: 13
- FWCI
- 3.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- German Medical Science (German Research Foundation) (publishedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion)
- German Medical Science (German Research Foundation)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (58108)
- U.S. Public Health Service (58108)
- National Heart, Lung, and Blood Institute (R01HL058108)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- platelet factor 4, CD163, macrophage differentiation, atherogenesis, heme oxygenase-1, hemoglobin-haptoglobin complex, glycosaminoglycans, heparin, ApoE-deficient mice
- MeSH terms
- CD68 Molecule, CD163 Antigen, Animals, Apolipoproteins E, Cell Differentiation, Gene Expression Regulation, Hemoglobins, Humans, Macrophages, Monocytes, Platelet Factor 4, Receptors, Cell Surface, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Mice, Knockout, Atherosclerosis, Receptors, Scavenger, Mice, Heme Oxygenase-1
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