Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.
File(s)
Published version
Author(s)
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.
Date Issued
2017-09-19
Date Acceptance
2017-06-13
Citation
Circulation, 2017, 136 (12), pp.1140-1154
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.
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.
License URL
Sponsor
British Heart Foundation
British Heart Foundation
Identifier
PII: CIRCULATIONAHA.117.027844
Grant Number
RG/11/13/29055
PG/15/49/31595
Subjects
CD11c
IRF5
atherosclerosis
efferocytosis
macrophages
Publication Status
Published