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

Seneviratne, Anusha N.; Edsfeldt, Andreas LU ; Cole, Jennifer E.; Kassiteridi, Christina; Swart, Maarten; Park, Inhye; Green, Patricia; Khoyratty, Tariq; Saliba, David and Goddard, Michael E, et al. (2017) In Circulation 136(5). p.1140-1154
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 two complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE) mice and ApoE mice with a genetic deletion of IRF5 (ApoEIrf5) was compared then... (More)

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 two complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE) mice and ApoE mice with a genetic deletion of IRF5 (ApoEIrf5) was compared then lesion development was assessed in a model of shear stress modulated vulnerable plaque formation. RESULTS—: Both lesion size and necrotic core size were significantly reduced in ApoEIrf5 mice compared to 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 ApoEIrf5 mice in the aorta, draining lymph nodes and in 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-EGF factor 8 protein (Mfge8) and enhanced efferocytosis in vitro and in situ. CONCLUSIONS—: IRF5 is detrimental in atherosclerosis by promoting the maintenance of pro-inflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.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.

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Circulation
volume
136
issue
5
pages
1140 - 1154
publisher
Lippincott Williams and Wilkins
external identifiers
  • scopus:85024483493
  • wos:000410925300007
ISSN
0009-7322
DOI
10.1161/CIRCULATIONAHA.117.027844
language
English
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yes
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94d4d17f-019e-4340-8ca4-3a506686e742
date added to LUP
2017-08-02 12:13:36
date last changed
2018-04-08 04:59:33
@article{94d4d17f-019e-4340-8ca4-3a506686e742,
  abstract     = {<p>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 two complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE) mice and ApoE mice with a genetic deletion of IRF5 (ApoEIrf5) was compared then lesion development was assessed in a model of shear stress modulated vulnerable plaque formation. RESULTS—: Both lesion size and necrotic core size were significantly reduced in ApoEIrf5 mice compared to 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 ApoEIrf5 mice in the aorta, draining lymph nodes and in 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-EGF factor 8 protein (Mfge8) and enhanced efferocytosis in vitro and in situ. CONCLUSIONS—: IRF5 is detrimental in atherosclerosis by promoting the maintenance of pro-inflammatory CD11c+ macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.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.</p>},
  author       = {Seneviratne, Anusha N. and Edsfeldt, Andreas and Cole, Jennifer E. and Kassiteridi, Christina and Swart, Maarten and Park, Inhye and Green, Patricia and Khoyratty, Tariq and Saliba, David and Goddard, Michael E and Sansom, Stephen N. and Goncalves, Isabel and Krams, Rob and Udalova, Irina A. and Monaco, Claudia},
  issn         = {0009-7322},
  language     = {eng},
  month        = {07},
  number       = {5},
  pages        = {1140--1154},
  publisher    = {Lippincott Williams and Wilkins},
  series       = {Circulation},
  title        = {Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis},
  url          = {http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027844},
  volume       = {136},
  year         = {2017},
}