CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis

• Published in: Nature (London) Vol. 536; no. 7614; pp. 86 - 90
• Main Authors: Kojima, Yoko, Volkmer, Jens-Peter, McKenna, Kelly, Civelek, Mete, Lusis, Aldons Jake, Miller, Clint L., Direnzo, Daniel, Nanda, Vivek, Ye, Jianqin, Connolly, Andrew J., Schadt, Eric E., Quertermous, Thomas, Betancur, Paola, Maegdefessel, Lars, Matic, Ljubica Perisic, Hedin, Ulf, Weissman, Irving L., Leeper, Nicholas J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.08.2016; Nature Publishing Group
• Subjects: 13; 13/1; 13/106; 13/31; 14/105; 38; 38/61; 631/154/555; 631/208/199; 631/80/304; 64; 64/60; 692/699/75/593/2100; 82; Analysis; Animals; Antibodies; Antibodies, Blocking - immunology; Antibodies, Blocking - pharmacology; Apoptosis; Atherosclerosis; Atherosclerosis - metabolism; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Atherosclerosis - therapy; Cardiovascular diseases; Carotid Arteries - pathology; CD47 Antigen - biosynthesis; CD47 Antigen - immunology; CD47 Antigen - metabolism; Cells; Coronary Vessels - pathology; Cytokines; Disease Models, Animal; Female; Genomes; Health aspects; Humanities and Social Sciences; Humans; Immunoglobulins; letter; Male; Mice; multidisciplinary; NF-kappa B - metabolism; Phagocytosis - drug effects; Prevention; Protein Biosynthesis; Science; Studies; Tumor Necrosis Factor-alpha - metabolism; Up-Regulation; Vascular diseases; Viral antibodies; United States
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature18935

Atherosclerotic lesions in mice and humans switch on a ‘don’t eat me’ signal—expression of CD47—that prevents effective removal of diseased tissue; anti-CD47 antibody therapy can normalize this defective efferocytosis, with beneficial results in several mouse models of atherosclerosis. Pathogenesis mechanisms in atherosclerosis Nicholas Leeper and colleagues demonstrate that atherosclerotic lesions in mice and humans switch on a 'don't eat me' signal — in the form of expression of the anti-phagocytic transmembrane protein CD47 — that prevents effective removal of diseased tissue. They show that administration of anti-CD47 antibodies can normalize this defective phagocytic clearance (or ‘efferocytosis’) with beneficial results in several mouse models of atherosclerosis. These results suggest that targeted pro-efferocytic therapies could have potential in cardiovascular diseases. Atherosclerosis is the disease process that underlies heart attack and stroke 1 . Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris 2 . Why these cells are not cleared remains unknown 3 . 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’ 4 , 5 , 6 , 7 . 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 5 , impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.