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.

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.

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-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ.

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.