Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization
. Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of
is protective against atherosclerosis.
mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques.
deficiency blunted LPS/IFNγ-induced inflammatory gene expression
and in the atherosclerotic aorta
. While atherosclerotic lesion size was not reduced in myeloid cell-specific
mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated
deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment.
-deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and
-deficient macrophages proliferated less in the plaque.
Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.