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Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.

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Title: Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.
Authors: Seneviratne, AN
Edsfeldt, A
Cole, JE
Kassiteridi, C
Swart, M
Park, I
Green, P
Khoyratty, T
Saliba, D
Goddard, ME
Sansom, SN
Goncalves, I
Krams, R
Udalova, IA
Monaco, C
Item Type: Journal Article
Abstract: BACKGROUND: Myeloid cells are central to atherosclerotic lesion development and vulnerable plaque formation. Impaired ability of arterial phagocytes to uptake apoptotic cells (efferocytosis) promotes lesion growth and establishment of a necrotic core. The transcription factor interferon regulatory factor (IRF)-5 is an important modulator of myeloid function and programming. We sought to investigate whether IRF5 affects the formation and phenotype of atherosclerotic lesions. METHODS: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE(-/-)) mice and ApoE(-/-) mice with a genetic deletion of IRF5 (ApoE(-/-)Irf5(-/-)) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation. RESULTS: Both lesion and necrotic core size were significantly reduced in ApoE(-/-)Irf5(-/-) mice compared with IRF5-competent ApoE(-/-) mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c(+) macrophages was evident in ApoE(-/-)Irf5(-/-) mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c(+) macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c(-) macrophages displayed a significant increase in expression of the efferocytosis-regulating integrin-β3 and its ligand milk fat globule-epidermal growth factor 8 protein and enhanced efferocytosis in vitro and in situ. CONCLUSIONS: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c(+) macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.
Issue Date: 19-Sep-2017
Date of Acceptance: 13-Jun-2017
URI: http://hdl.handle.net/10044/1/51476
DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.117.027844
ISSN: 0009-7322
Publisher: American Heart Association
Start Page: 1140
End Page: 1154
Journal / Book Title: Circulation
Volume: 136
Issue: 12
Copyright Statement: © 2017 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: British Heart Foundation
British Heart Foundation
Funder's Grant Number: RG/11/13/29055
PG/15/49/31595
Keywords: CD11c
IRF5
atherosclerosis
efferocytosis
macrophages
1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
1117 Public Health And Health Services
Cardiovascular System & Hematology
Publication Status: Published
Appears in Collections:Faculty of Engineering
Bioengineering
National Heart and Lung Institute
Faculty of Medicine



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