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Interferon Regulatory Factor 5 Controls Necrotic Core Formation in Atherosclerotic Lesions by Impairing Efferocytosis
Open accessAbstract
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.
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“The impaired ability of macrophage efferocytosis would enhance atherogenesis [139,140,141] and atherosclerotic plaque instability [142,143,144].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [142]
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“interferon regulatory factor 5 (IRF5) transcription factor enhances vulnerable plaque formation in hyperlipidemic apolipoprotein E-deficient (ApoE−/−) mice through the induction of pro-inflammatory CD11c+ macrophages within atherosclerotic lesions and increasing the expansion of the necrotic core by inhibiting macrophage efferocytosis [142].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [142]
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Metadata
- Authors
- Seneviratne, A. N., Edsfeldt, A., Cole, J. E., Kassiteridi, C., Swart, M., Park, I., Green, P., Khoyratty, T., Saliba, D., Goddard, M. E., Sansom, S. N., Goncalves, I., Krams, R., Udalova, I. A., & Monaco, C.
- Affiliations
- Queen Mary University of London (GB)
- From Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, United Kingdom (A.N.S., A.E., J.E.C., C.K., M.S., I.P., P.G., T.K., D.S., M.E.G., S.N.S., I.A.U., C.M.); Department of Bioengineering, Imperial College London, United Kingdom (A.N.S., R.K.); Experimental Cardiovascular Research Unit, Clinical Research Centre, Clinical Sciences Malmö, Lund University, Sweden (A.E., I.G.); Department of Cardiology, Skåne...
- Corresponding author
- Monaco, Claudia
- ORCID
- Venue
- Circulation
- Published
- 2017-09-19
- Volume
- 136
- Issue
- 12
- Pages
- 1140-1154
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC5598917
- OpenAlex
- W2735394628
- Cited by
- 117
- References
- 40
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 12 · 2023: 8 · 2022: 15 · 2021: 16 · 2020: 14 · 2019: 10 · 2018: 9 · 2017: 1
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Circulation (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion, cc-by)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Funders
- Kennedy Trust for Rheumatology Research (KENN161701)
- British Heart Foundation (PG/15/49/31595, RG/11/13/29055)
- Novo Nordisk Fonden (NNF15SA0018346, NNF15SA0018486)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Keywords
- IRF5, atherosclerosis, necrotic core, efferocytosis, CD11c+ macrophages, CD61, MFG-E8, vulnerable plaque, shear stress, ApoE-deficient mice, transcriptional regulation
- MeSH terms
- Animals, Aorta, Apolipoproteins E, Bone Marrow Cells, Cells, Cultured, Immunohistochemistry, Lymph Nodes, Macrophages, Mice, Inbred C57BL, Necrosis, Phagocytosis, Mice, Knockout, Shear Strength, CD11c Antigen, Integrin beta3, Atherosclerosis, Interferon Regulatory Factors, Mice
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