Shear stress and interferon regulatory gactor 5 modulate myeloid cell behaviour in atherosclerosis

Abstract

Rupture of “vulnerable” atherosclerotic plaques and subsequent thrombosis cause acute cardiovascular events, and can develop upon exposure of the arterial wall to low shear stress. Myeloid cells - the main inflammatory cells within atherosclerotic plaques - are heterogeneous; ranging from “classical” pro-inflammatory M1 macrophages to “alternative” M2 macrophages and various subsets of dendritic cells. The activation of Toll-like receptors and downstream Interferon Regulatory Factors (IRFs) is involved in atherosclerosis. IRF5 polarises macrophages towards the M1 phenotype and modulates cytokine production by dendritic cells. I utilised two murine models of atherosclerosis: the hypercholesterolaemic ApoE-/- (Apolipoprotein E knockout) mouse strain, and a perivascular cast modifying shear stress patterns in the carotid artery. Firstly, I found the majority of macrophages in early and intermediate lesions of the aortic root and advanced oscillatory shear stress-modulated lesions express heme oxygenase-1 (HO-1). The representation of the M1 macrophage marker iNOS (inducible nitric oxide synthase) and IRF5 is more prevalent in low shear stress-modulated plaques, which resemble a vulnerable plaque, while M2 macrophage markers are elevated in oscillatory shear stress-modulated plaques resembling stable plaques. Secondly, I studied the effect of IRF5 deletion on the development of atherosclerosis by comparing the severity of atherosclerosis in ApoE-/- mice with ApoE-/-IRF5-/- mice. Atherosclerotic lesions in the aortic root of ApoE-/-IRF5-/- mice are reduced in size, and in all vascular regions they have smaller necrotic cores (a marker of plaque vulnerability), due to a reduction in efferocytosis, and an increase in atheroprotective macrophages. Lesions in ApoE-/-IRF5-/- mice also have a depleted content of cells expressing CD11c; therefore IRF5 is detrimental in atherosclerosis by skewing myeloid cell differentiation towards dendritic cells possibly via GM-CSF. My study provides a novel link between inflammatory signalling, efferocytosis and necrotic core formation.