CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.
CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.
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DOI：
10.1038/nature18935
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发表时间：
2016-08-04
期刊：
影响因子：
64.8
通讯作者：
Leeper NJ
中科院分区：
文献类型：
--
作者：
Kojima Y;Volkmer JP;McKenna K;Civelek M;Lusis AJ;Miller CL;Direnzo D;Nanda V;Ye J;Connolly AJ;Schadt EE;Quertermous T;Betancur P;Maegdefessel L;Matic LP;Hedin U;Weissman IL;Leeper NJ
动脉粥样硬化是引发心脏病发作和中风的疾病过程。有破裂风险的晚期病变的特征是病变血管细胞和凋亡细胞碎片的病理性堆积。为何这些细胞未被清除仍然未知。在此我们表明，动脉粥样硬化形成与CD47的上调相关，CD47是一种关键的“别吃我”分子，已知其可使恶性细胞对程序性细胞清除（PrCR，即胞葬作用）产生抗性。我们发现，给予CD47阻断抗体可逆转胞葬作用的这一缺陷，使病变血管组织的清除恢复正常，并改善多种小鼠模型中的动脉粥样硬化。机制研究表明，促动脉粥样硬化因子肿瘤坏死因子 -α是PrCR受损的根本驱动因素，这解释了为何这一过程在血管疾病中受到损害。与近期在癌症中的观察结果相似，胞葬作用受损似乎在心血管疾病中起致病作用，但并非是一种固定的缺陷，可能代表一个新的治疗靶点。
Atherosclerosis is the disease process underlying heart attack and stroke. Advanced lesions at risk for 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 ‘don’t eat me’ molecule known to render malignant cells resistant to programmed cell removal (PrCR), 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 PrCR, 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.