Background: Interferon regulatory factor (IRF) 5 is a transcription factor promoting inflammatory macrophage polarization (M1 type). Given the central role of macrophages in atherosclerotic plaque development we hypothesized that macrophage specific deletion of IRF5 will protect from atherosclerosis.

Methods: Female Apoe^-/- LysM^Cre/wt IRF5^flox/flox and Apoe^-/- LysM^wt/wt IRF5^flox/flox mice were fed a high cholesterol diet for 3 months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependend bone marrow derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Aortic macrophage chimerism in irradiated ApoE-/- mice reconstituted with a mixture of CD45.1+ ApoE-/- (WT) and CD45.2+ Apoe^-/- LysM^Cre/Wt IRF5^flox/flox(KO) bone marrow was evaluated in early and advanced atherosclerosis to distinguish systemic from intra-plaque effects on monocyte/macrophage kinetics. 

Results: Macrophage-specific IRF5 deficiency did not impact lesion size in the aortic root but significantly reduced macrophage and lipid contents while increasing collagen deposition. Moreover, inflammation in the aorta was attenuated. When competing with WT cells in mixed irradiation bone marrow chimeras, IRF5 deficient macrophages showed as disadvantage in accumulating in atherosclerotic aortas as disease progressed independent of monocyte recruitment. IRF5-deficient bone-marrow derived macrophages expressed less pro-inflammatory cytokines and more efferocytosis mediating MerTK expression.

Conclusion: Transcription factor IRF5 promotes a pro-inflammatory response in macrophages leading to vulnerable plaque formation and plaque destabilization.