Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis

Article

关键词: APOPTOTIC CELL ACCUMULATION;    COLONY-STIMULATING FACTOR;    MACROPHAGE POLARIZATION;    GENE;    DEFICIENCY;    TISSUE;    LIPOPOLYSACCHARIDE;    PHAGOCYTOSIS;    ACTIVATION;    EXPRESSION;   

DOI  :  10.1161/CIRCULATIONAHA.117.027844

来源: SCIE

【 摘 要 】

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-beta 3 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.

【 授权许可】

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