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Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis.
- Source :
-
Circulation [Circulation] 2017 Sep 19; Vol. 136 (12), pp. 1140-1154. Date of Electronic Publication: 2017 Jul 11. - Publication Year :
- 2017
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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.<br />Methods: We investigated the role of IRF5 in atherosclerosis in 2 complementary models. First, atherosclerotic lesion development in hyperlipidemic apolipoprotein E-deficient (ApoE <superscript>-/-</superscript> ) mice and ApoE <superscript>-/-</superscript> mice with a genetic deletion of IRF5 (ApoE <superscript>-/-</superscript> Irf5 <superscript>-/-</superscript> ) was compared and then lesion development was assessed in a model of shear stress-modulated vulnerable plaque formation.<br />Results: Both lesion and necrotic core size were significantly reduced in ApoE <superscript>-/-</superscript> Irf5 <superscript>-/-</superscript> mice compared with IRF5-competent ApoE <superscript>-/-</superscript> mice. Necrotic core size was also reduced in the model of shear stress-modulated vulnerable plaque formation. A significant loss of CD11c <superscript>+</superscript> macrophages was evident in ApoE <superscript>-/-</superscript> Irf5 <superscript>-/-</superscript> mice in the aorta, draining lymph nodes, and bone marrow cell cultures, indicating that IRF5 maintains CD11c <superscript>+</superscript> macrophages in atherosclerosis. Moreover, we revealed that the CD11c gene is a direct target of IRF5 in macrophages. In the absence of IRF5, CD11c <superscript>-</superscript> 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.<br />Conclusions: IRF5 is detrimental in atherosclerosis by promoting the maintenance of proinflammatory CD11c <superscript>+</superscript> macrophages within lesions and controlling the expansion of the necrotic core by impairing efferocytosis.<br /> (© 2017 The Authors.)
- Subjects :
- Animals
Aorta metabolism
Aorta pathology
Apolipoproteins E deficiency
Apolipoproteins E genetics
Atherosclerosis metabolism
Bone Marrow Cells cytology
Bone Marrow Cells metabolism
CD11c Antigen genetics
CD11c Antigen metabolism
Cells, Cultured
Immunohistochemistry
Integrin beta3 metabolism
Interferon Regulatory Factors deficiency
Interferon Regulatory Factors genetics
Lymph Nodes cytology
Macrophages cytology
Macrophages metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Necrosis
Phagocytosis
Shear Strength
Atherosclerosis pathology
Interferon Regulatory Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 136
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 28698173
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.117.027844