CXCL4 downregulates the atheroprotective hemoglobin receptor CD163 in human macrophages.
Circ Res
; 106(1): 203-11, 2010 Jan 08.
Article
en En
| MEDLINE
| ID: mdl-19910578
ABSTRACT
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 ANDRESULTS:
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Factor Plaquetario 4
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Antígenos de Diferenciación Mielomonocítica
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Antígenos CD
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Receptores de Superficie Celular
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Aterosclerosis
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Receptores Depuradores
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Macrófagos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Circ Res
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos