Document Detail

CXCL4 downregulates the atheroprotective hemoglobin receptor CD163 in human macrophages.
MedLine Citation:
PMID:  19910578     Owner:  NLM     Status:  MEDLINE    
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.
Christian A Gleissner; Iftach Shaked; Christian Erbel; Dittmar Böckler; Hugo A Katus; Klaus Ley
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2009-11-12
Journal Detail:
Title:  Circulation research     Volume:  106     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 Jan 
Date Detail:
Created Date:  2010-01-08     Completed Date:  2010-01-22     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  203-11     Citation Subset:  IM    
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MeSH Terms
Antigens, CD / biosynthesis*,  genetics,  metabolism
Antigens, Differentiation, Myelomonocytic / biosynthesis*,  genetics,  metabolism
Apolipoproteins E / genetics,  metabolism
Atherosclerosis / genetics,  metabolism*
Cell Differentiation / drug effects,  genetics
Gene Expression Regulation / drug effects,  genetics
Heme Oxygenase-1 / biosynthesis,  genetics
Hemoglobins / genetics,  metabolism,  pharmacology
Macrophages / metabolism*
Mice, Knockout
Monocytes / metabolism
Platelet Factor 4 / genetics,  metabolism*,  pharmacology
Receptors, Cell Surface / biosynthesis*,  genetics,  metabolism
Receptors, Scavenger / agonists,  biosynthesis*,  genetics
Grant Support
58108//PHS HHS; R01 HL058108/HL/NHLBI NIH HHS; R01 HL058108-09/HL/NHLBI NIH HHS; R01 HL058108-10/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, Differentiation, Myelomonocytic; 0/Apolipoproteins E; 0/CD163 antigen; 0/CD68 antigen, human; 0/Hemoglobins; 0/Receptors, Cell Surface; 0/Receptors, Scavenger; 37270-94-3/Platelet Factor 4; EC Oxygenase-1

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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