| First Author | Seneviratne AN | Year | 2017 |
| Journal | Circulation | Volume | 136 |
| Issue | 12 | Pages | 1140-1154 |
| PubMed ID | 28698173 | Mgi Jnum | J:266953 |
| Mgi Id | MGI:6257314 | Doi | 10.1161/CIRCULATIONAHA.117.027844 |
| Citation | Seneviratne AN, et al. (2017) Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis. Circulation 136(12):1140-1154 |
| abstractText | 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-beta3 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. |
