title: CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.
abstract: 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.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kojima
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Volkmer
authors.forename: Kelly
authors.initials: K
authors.lastname: McKenna
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.forename: Aldons Jake
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Clint L
authors.initials: CL
authors.lastname: Miller
authors.forename: Daniel
authors.initials: D
authors.lastname: Direnzo
authors.forename: Vivek
authors.initials: V
authors.lastname: Nanda
authors.forename: Jianqin
authors.initials: J
authors.lastname: Ye
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Connolly
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.forename: Thomas
authors.initials: T
authors.lastname: Quertermous
authors.forename: Paola
authors.initials: P
authors.lastname: Betancur
authors.forename: Lars
authors.initials: L
authors.lastname: Maegdefessel
authors.forename: Ljubica Perisic
authors.initials: LP
authors.lastname: Matic
authors.forename: Ulf
authors.initials: U
authors.lastname: Hedin
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Leeper
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000276:immunology* / Q000494:pharmacology*; D017209:Apoptosis; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D051928:CD47 Antigen / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D002339:Carotid Arteries / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects*; D014176:Protein Biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D051928:CD47 Antigen; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha