RESUMO
[Figure: see text].
Assuntos
Antígenos CD/metabolismo , Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Quimiotaxia de Leucócito , Leucopoese , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos CD/genética , Aorta/imunologia , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/imunologia , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Células Cultivadas , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/imunologia , Doença da Artéria Coronariana/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Monócitos/imunologia , Receptores de Orexina/metabolismo , Fosforilação , Placa Aterosclerótica , Fator de Transcrição STAT1/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. METHODS: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE-/-) mice and ApoE-/- mice with a genetic deletion of IRF5 (ApoE-/-Irf5-/-) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation. RESULTS: Both lesion and necrotic core size were significantly reduced in ApoE-/-Irf5-/- mice compared with IRF5-competent ApoE-/- mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c+ macrophages was evident in ApoE-/-Irf5-/- mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c+ macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c- macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-ß3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ. CONCLUSIONS: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.
Assuntos
Aterosclerose/patologia , Fatores Reguladores de Interferon/metabolismo , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Antígeno CD11c/genética , Antígeno CD11c/metabolismo , Células Cultivadas , Imuno-Histoquímica , Integrina beta3/metabolismo , Fatores Reguladores de Interferon/deficiência , Fatores Reguladores de Interferon/genética , Linfonodos/citologia , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Fagocitose , Resistência ao CisalhamentoRESUMO
Macrophages, a significant component of atherosclerotic plaques vulnerable to acute complications, can be pro-inflammatory (designated M1), regulatory (M2), lipid- (Mox) or Heme-induced (Mhem). We showed previously that low (LSS) and oscillatory (OSS) shear stress cause thin-cap fibroatheroma and stable smooth muscle cell-rich plaque formation respectively in ApoE-knockout (ApoE(-/-)) mice. Here we investigated whether different shear stress conditions relate to specific changes in macrophage polarization and plaque morphology by applying a shear stress-altering cast to the carotid arteries of high fat-fed ApoE(-/-) mice. The M1 markers iNOS and IRF5 were highly expressed in macrophage-rich areas of LSS lesions compared to OSS lesions 6weeks after cast placement, while the M2 marker Arginase-1, and Mox/Mhem markers HO-1 and CD163 were elevated in OSS lesions. Our data indicates shear stress could be an important determinant of macrophage polarization in atherosclerosis, with low shear promoting M1 programming.
Assuntos
Polaridade Celular , Macrófagos/patologia , Placa Aterosclerótica/patologia , Resistência ao Cisalhamento , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Biomarcadores/metabolismo , Artérias Carótidas/patologia , Feminino , Camundongos Endogâmicos C57BLRESUMO
The primary cause of cerebrovascular disease is atherosclerosis, to which many factors contribute. At first many saw atherosclerosis as a lipid-driven disease. Recently inflammation has appeared as a significant factor in the disease. Innate immune cells, for example monocytes and macrophages, are important in atherosclerosis. Toll-like receptors (TLRs) are the best-studied family of receptor in the immune system. TLR engagement with their ligands stimulates pro-inflammatory cytokine production and foam cell generation. Recently certain TLRs have shown a protective role in atherosclerosis. In this review, we analyse innate immunity, focusing on TLR signalling and macrophages, in atherosclerosis and acute cerebrovascular complications, and thereby discuss their potential as therapeutic targets.