CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis

Abstract

Summary Atherosclerosis is the disease process underlying heart attack and stroke1. Advanced lesions at risk for rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris2. Why these cells are not cleared remains unknown3. Here we show that atherogenesis is associated with upregulation of CD47, a key ‘don’t eat me’ molecule known to render malignant cells resistant to programmed cell removal (PrCR), or ‘efferocytosis’4–7. 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 PrCR, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer5, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.

MerTK receptor cleavage promotes plaque necrosis and defective resolution in atherosclerosis

“…Data from human and mouse studies suggest that plaque necrosis results from 2 complementary processes, postapoptotic necrosis secondary to defective efferocytosis as examined here (2, 3) and a primary cell necrosis process called necroptosis (27,28). While the current study is focused on an efferocytosis defect in phagocytes themselves, a recent study showed that some apoptotic cells in human and mouse lesions inappropriately retain CD47, which blocks their engulfment by normal phagocytes (29). Interestingly, oxLDL, which was shown here to promote MerTK cleavage and defective efferocytosis, can induce necroptosis in macrophages, and these cells are also poorly Two such proteins, TGF-β1 and IL-10, were significantly increased in Mertk CR plasma (Supplemental Figure 6A).…”

Unifying mechanism for different fibrotic diseases

“…We showed that fibrogenic cells expressed high levels of the self-protective don't-eat-me epitope CD47. It had been shown in various solid cancers and hematopoietic malignancies, and most recently in atherosclerosis, that blockade of CD47 by antibodies or artificial, high-affinity Sirpα analogs prevents this repressive signal in macrophages, leading to their activation and active phagocytosis (24). The remarkable low toxicity of anti-CD47 treatments, however, suggested that additional alterations in cancer cells are required to induce phagocytosis (21,25).…”

X-Box Binding Protein-1 Dependent Plasma Cell Responses Limit the Development of Atherosclerosis

“…59,60 Recently, increased antiphagocytic CD47 on the surface of plaque cells and loss of surface Mer tyrosine kinase on plaque phagocytes have been shown to play important roles in mouse and human atherosclerosis. 61,62 These defects lead to secondary necrosis, making cells and oxLDL debris recognizable to anti-MDA and anti-phosphorylcholine antibodies. These antibodies provide an alternate protective layer that is nevertheless insufficient to prevent atherosclerosis progression; however, the lack of such antibodies greatly accelerates plaque growth.…”