Department of Biochemistry, Cardiovascular Research Institute Maastricht, University of Maastricht, Maastricht 6200 MD, The Netherlands.
Cell Death Differ. 2013 Jan;20(1):49-56. doi: 10.1038/cdd.2012.107. Epub 2012 Sep 7.
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 α(v)β(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.
吞噬作用受损已被证明与慢性炎症性疾病（如动脉粥样硬化）的进展有关，甚至与之有关。增强吞噬作用已被提议作为治疗涉及炎症的疾病的策略。在这里，我们提出了一种通过靶向细胞表面表达的磷脂酰丝氨酸（PS）来增加“被吞噬”信号的策略，方法是使用一种获得与吞噬细胞α(v)β(3)受体相互作用功能的 annexin A5（Arg-Gly-Asp-annexin A5，RGD-anxA5）变体。我们描述了 RGD-anxA5 的设计和特性，并表明引入 RGD 将 anxA5 从吞噬作用的抑制剂转变为刺激剂。RGD-anxA5 增强了佛波醇 12-肉豆蔻酸 13-乙酸刺激的 THP-1（人急性单核细胞白血病细胞系）细胞和体内驻留的腹膜巨噬细胞体外对凋亡细胞的吞噬作用。此外，RGD-anxA5 增加了体内吞噬作用过程中白细胞介素-10 的分泌，从而可能增加抗炎环境。我们得出结论，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，而合理设计的 RGD-anxA5 是一种有前途的治疗剂。
