Inflammation was an essential component of atherosclerosis. Macrophages were induced to a pro-inflammatory state by the transcription factor interferon regulatory factor-5 (IRF5). For a study, the researchers investigated the function of IRF5 in human atherosclerosis and plaque stability for an outline. The Carotid Plaque Imaging Project’s biobank was used to examine associations between primary macrophage-associated genes and transcription factors and human symptomatic carotid disease. Immunohistochemistry, proximity extension assays, and Helios cytometry by time of flight (CyTOF) were utilized for validation. An inducible model of plaque rupture was used to go through the effect of IRF5 deficiency on carotid plaque phenotype and rupture in ApoE−/− mice. Interferon regulatory factor-5 and ITGAX/CD11c were determined as the macrophage-associated genes with the most significant associations with symptomatic carotid disease. The detection of IRF5 and ITGAX/CD11c was associated with the vulnerability index, pro-inflammatory plaque cytokine levels, necrotic core area, and each other. By CyTOF, macrophages were the most frequent CD11c-expressing immune cells in the plaque. Interferon regulatory factor-5 immunopositive areas were primarily observed in CD11c+ regions with a preference for the shoulder region, where the human plaque’s most vulnerable to rupture is. To assess whether IRF5 plays a role in plaque rupture, the researchers used induced plaque rupture models of ApoE−/degree/mice and Irf5-deficient mice. CD11c+ macrophages were significantly lower in the former group, and smaller necrotic cores and fewer carotid plaque ruptures. In IRF5-deficient mice, carotid plaque rupture induced by amyloid was reduced when the researchers combined data from human endarterectomies and a murine model of inducible ruptured plaques. The researchers demonstrated a mechanistic link between pro-inflammatory transcription factor IRF5, macrophage phenotype, plaque inflammation, and plaque vulnerability to rupture.