CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis
Open accessAbstract
Atherosclerosis is the disease process that underlies heart attack and stroke. Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Why these cells are not cleared remains unknown. Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or 'efferocytosis'. We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.
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CD47-blocking antibodies given to Apoe−/− mice on a high-fat diet increase lesional efferocytosis and reduce necrotic core formation.
“Accordingly, delivery of CD47-blocking antibodies to Apoe−/− mice fed a high-fat diet increases efferocytosis in the atherosclerotic lesion and reduces necrotic core formation207.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [207]
Apoptotic cells in plaques from patients with symptomatic cerebrovascular disease have higher surface CD47 than non-atherosclerotic vascular tissue.
“Supporting the concept that apoptotic cells can inappropriately disrupt efferocytosis, apoptotic cells in atherosclerotic plaques from patients with symptomatic cerebrovascular disease have increased levels of the TNF-dependent, ‘don’t-eat-me’ signal CD47 on the cell surface compared with non-atherosclerotic vascular tissue207.”
From Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities (2019) · cites this paper as [207]
Antibodies blocking CD47 reactivate efferocytosis of diseased vascular tissue without altering cellular apoptosis, as well as alleviate atherosclerosis in both aortic sinus and en face of aorta in multiple mouse models.
“Antibodies blocking CD47 reactivate efferocytosis of diseased vascular tissue without altering cellular apoptosis, as well as alleviate atherosclerosis in both the aortic sinus and en face of the aorta in multiple mouse models [148].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [148]
Apoptotic or senescent cells have increased expression of cell-surface protein CD47, one of the "don't eat me" signals, which impairs efferocytosis via binding to inhibitory receptor SIRPα on macrophage.
“apoptotic or senescent cells have increased expression of cell-surface protein CD47, one of the “don’t eat me” signals, which impairs efferocytosis via binding to the inhibitory receptor signal regulatory protein alpha (SIRPα) on the macrophage.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [148]
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- Authors
- Kojima, Y., Volkmer, J.-P., McKenna, K., Civelek, M., Lusis, A. J., Miller, C. L., Direnzo, D., Nanda, V., Ye, J., Connolly, A. J., Schadt, E. E., Quertermous, T., Betancur, P., Maegdefessel, L., Matic, L. P., Hedin, U., Weissman, I. L., & Leeper, N. J.
- Affiliations
- Stanford Medicine (US)
- Institute for Stem Cell Biology and Regenerative Medicine (US)
- University of California, Los Angeles (US)
- Icahn School of Medicine at Mount Sinai (US)
- Karolinska Institutet (SE)
- Corresponding author
- Leeper, Nicholas J.
- ORCID
- Venue
- Nature
- Published
- 2016-07-20
- Volume
- 536
- Issue
- 7614
- Pages
- 86-90
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4980260
- OpenAlex
- W2497350880
- Cited by
- 683
- References
- 43
- Citations by year
- 2026: 73 · 2025: 90 · 2024: 93 · 2023: 74 · 2022: 83 · 2021: 62 · 2020: 58 · 2019: 52 · 2018: 38 · 2017: 40 · 2016: 14 · 2015: 2
- FWCI
- 29.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01 HL12522401, R01HL125224, R01HL123370, R01HL109512, U01HL099999, R33HL120757, R01HL12337001, T32HL098049, T32HL094274)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- CD47, anti-CD47 antibody, efferocytosis, phagocytosis, atherosclerosis, don't eat me signal, TNF-α, atherosclerotic plaque, cardiovascular disease treatment
- MeSH terms
- Animals, Carotid Arteries, Coronary Vessels, Disease Models, Animal, Female, Humans, Male, Phagocytosis, Protein Biosynthesis, Tumor Necrosis Factor-alpha, Up-Regulation, NF-kappa B, Apoptosis, Antibodies, Blocking, Atherosclerosis, Mice, CD47 Antigen
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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