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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 two 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 then lesion development was assessed in a model of shear stress modulated vulnerable plaque formation. Results -Both lesion size and necrotic core size were significantly reduced in ApoE(-/-)Irf5(-/-) mice compared to 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 in 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-β3 and its ligand milk fat globule-EGF factor 8 protein (Mfge8) and enhanced efferocytosis in vitro and in situConclusions -IRF5 is detrimental in atherosclerosis by promoting the maintenance of pro-inflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.

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atherosclerosis, inflammation, macrophage