Compartmentalized protective and detrimental effects of endogenous macrophage migration-inhibitory factor mediated by CXCR2 in a mouse model of myocardial ischemia/reperfusion.
Arterioscler Thromb Vasc Biol
; 33(9): 2180-6, 2013 Sep.
Article
em En
| MEDLINE
| ID: mdl-23868943
ABSTRACT
OBJECTIVE:
Here, we aimed to clarify the role of CXC chemokine receptor (CXCR) 2 in macrophage migration-inhibitory factor (MIF)-mediated effects after myocardial ischemia and reperfusion. As a pleiotropic chemokine-like cytokine, MIF has been identified to activate multiple receptors, including CD74 and CXCR2. In models of myocardial infarction, MIF exerts both proinflammatory effects and protective effects in cardiomyocytes. Similarly, CXCR2 displays opposing effects in resident versus circulating cells. APPROACH ANDRESULTS:
Using bone marrow transplantation, we generated chimeric mice with Cxcr2(-/-) bone marrow-derived inflammatory cells and wild-type (wt) resident cells (wt/Cxcr2(-/-)), Cxcr2(-/-) cardiomyocytes and wt bone marrow-derived cells (Cxcr2(-/-)/wt), and wt controls reconstituted with wt bone marrow (wt/wt). All groups were treated with anti-MIF or isotype control antibody before they underwent myocardial ischemia and reperfusion. Blocking MIF increased infarction size and impaired cardiac function in wt/wt and wt/CXCR2(-/-) mice but ameliorated functional parameters in Cxcr2(-/-)/wt mice, as analyzed by echocardiography and Langendorff perfusion. Neutrophil infiltration and angiogenesis were unaltered by MIF blockade or Cxcr2 deficiency. Monocyte infiltration was blunted in wt/Cxcr2(-/-) mice and reduced by MIF blockade in wt/wt and Cxcr2(-/-)/wt mice. Furthermore, MIF blockade attenuated collagen content in all groups in a CXCR2-independent manner.CONCLUSIONS:
The compartmentalized and opposing effects of MIF after myocardial ischemia and reperfusion are largely mediated by CXCR2. Although MIF confers protective effects by improving myocardial healing and function through CXCR2 in resident cells, thereby complementing paracrine effects through CD74/AMP-activated protein kinase, it exerts detrimental effects on CXCR2-bearing inflammatory cells by increasing monocyte infiltration and impairing heart function. These dichotomous findings should be considered when developing novel therapeutic strategies to treat myocardial infarction.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Traumatismo por Reperfusão Miocárdica
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Fatores Inibidores da Migração de Macrófagos
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Mediadores da Inflamação
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Oxirredutases Intramoleculares
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Receptores de Interleucina-8B
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Miócitos Cardíacos
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Infarto do Miocárdio
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
Arterioscler Thromb Vasc Biol
Assunto da revista:
ANGIOLOGIA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Alemanha