Cell surface-expressed phosphatidylserine as therapeutic target to enhance phagocytosis of apoptotic cells
Cell surface-expressed phosphatidylserine as therapeutic target to enhance phagocytosis of apoptotic cells
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DOI：
10.1038/cdd.2012.107
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发表时间：
2013-01-01
影响因子：
12.4
通讯作者：
Reutelingsperger, C. P. M.
中科院分区：
文献类型：
--
作者：
Schutters, K.;Kusters, D. H. M.;Reutelingsperger, C. P. M.
泡泡吞噬功能受损已被证明与动脉粥样硬化等慢性炎症性疾病的进展有关，甚至有助于其进展。增强泡腾作用已被认为是治疗炎症相关疾病的策略。在这里，我们提出了一种策略，通过靶向细胞表面表达的磷脂酰丝氨酸(PS)和膜联蛋白A5的变体(Arg-Gly-Asp-Annexin A5，RGD-angA5)来增加凋亡细胞表面的“Eat Me”信号，该变体已经获得了与吞噬细胞的α(V)β(3)受体相互作用的功能。我们描述了RGD-XA5的设计和特性，并表明RGD的引入将XA5从抑制因子转变为泡饮刺激因子。RGD-XA5可促进佛波醇-12-肉豆蔻酸酯-13-乙酸酯刺激的人急性单核细胞白血病细胞系THP-1(人急性单核细胞白血病细胞系)和体内滞留的小鼠巨噬细胞吞噬凋亡细胞。此外，RGD-XA5在体内的吞噬作用中增加了IL-10的分泌，从而可能增加了抗炎环境。我们认为，靶向细胞表面表达的PS是治疗炎症性疾病的一种有吸引力的策略，设计合理的RGD-XA5是一种有前途的治疗剂。《细胞死亡与分化》(2013年)20，49-56；doi：10.1038/cdd.2012.107；2012年9月7日在线发布
Impaired efferocytosis has been shown to be associated with, and even to contribute to progression of, chronic inflammatory diseases such as atherosclerosis. Enhancing efferocytosis has been proposed as strategy to treat diseases involving inflammation. Here we present the strategy to increase 'eat me' signals on the surface of apoptotic cells by targeting cell surface-expressed phosphatidylserine (PS) with a variant of annexin A5 (Arg-Gly-Asp-annexin A5, RGD-anxA5) that has gained the function to interact with alpha(v)beta(3) receptors of the phagocyte. We describe design and characterization of RGD-anxA5 and show that introduction of RGD transforms anxA5 from an inhibitor into a stimulator of efferocytosis. RGD-anxA5 enhances engulfment of apoptotic cells by phorbol-12-myristate-13-acetate-stimulated THP-1 (human acute monocytic leukemia cell line) cells in vitro and resident peritoneal mouse macrophages in vivo. In addition, RGD-anxA5 augments secretion of interleukin-10 during efferocytosis in vivo, thereby possibly adding to an anti-inflammatory environment. We conclude that targeting cell surface-expressed PS is an attractive strategy for treatment of inflammatory diseases and that the rationally designed RGD-anxA5 is a promising therapeutic agent. Cell Death and Differentiation (2013) 20, 49-56; doi:10.1038/cdd.2012.107; published online 7 September 2012