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

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Title: Shear stress and interferon regulatory gactor 5 modulate myeloid cell behaviour in atherosclerosis
Authors: Seneviratne, Anusha Nilanthi
Item Type: Thesis or dissertation
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.
Content Version: Open Access
Issue Date: Jan-2014
Date Awarded: Apr-2014
URI: http://hdl.handle.net/10044/1/24853
http://hdl.handle.net/10044/1/45408
Supervisor: Monaco, Claudia
Krams, Rob
Sponsor/Funder: British Heart Foundation
Department: Medicine
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Medicine PhD theses



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