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首页> 美国卫生研究院文献>Cell Death and Differentiation >Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me signals: cleavage and inhibition of phagocytosis by Lp-PLA2
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Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic ‘eat-me signals: cleavage and inhibition of phagocytosis by Lp-PLA2

机译：凋亡细胞表面的氧化修饰磷脂酰丝氨酸是必不可少的吞噬吃我信号：Lp-PLA2裂解并抑制吞噬作用

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Diversified anionic phospholipids, phosphatidylserines (PS), externalized to the surface of apoptotic cells are universal phagocytic signals. However, the role of major PS metabolites, such as peroxidized species of PS (PSox) and lyso-PS, in the clearance of apoptotic cells has not been rigorously evaluated. Here, we demonstrate that H2O2 was equally effective in inducing apoptosis and externalization of PS in naive HL60 cells and in cells enriched with oxidizable polyunsaturated species of PS (supplemented with linoleic acid (LA)). Despite this, the uptake of LA-supplemented cells by RAW264.7 and THP-1 macrophages was more than an order of magnitude more effective than that of naive cells. A similar stimulation of phagocytosis was observed with LA-enriched HL60 cells and Jurkat cells triggered to apoptosis with staurosporine. This was due to the presence of PSox on the surface of apoptotic LA-supplemented cells (but not of naive cells). This enhanced phagocytosis was dependent on activation of the intrinsic apoptotic pathway, as no stimulation of phagocytosis occurred in LA-enriched cells challenged with Fas antibody. Incubation of apoptotic cells with lipoprotein-associated phospholipase A2 (Lp-PLA2), a secreted enzyme with high specificity towards PSox, hydrolyzed peroxidized PS species in LA-supplemented cells resulting in the suppression of phagocytosis to the levels observed for naive cells. This suppression of phagocytosis by Lp-PLA2 was blocked by a selective inhibitor of Lp-PLA2, SB-435495. Screening of possible receptor candidates revealed the ability of several PS receptors and bridging proteins to recognize both PS and PSox, albeit with diverse selectivity. We conclude that PSox is an effective phagocytic ‘eat-me' signal that participates in the engulfment of cells undergoing intrinsic apoptosis.
机译：外在凋亡细胞表面的各种阴离子磷脂，磷脂酰丝氨酸（PS）是通用的吞噬信号。但是，尚未严格评估主要PS代谢产物（例如PS的过氧化物质（PSox）和溶血PS）在清除凋亡细胞中的作用。在这里，我们证明了H2O2在天真HL60细胞和富含可氧化多不饱和PS的细胞（补充有亚油酸（LA））中诱导PS的凋亡和外在化同样有效。尽管如此，RAW264.7和THP-1巨噬细胞对LA补充细胞的摄取比幼稚细胞有效得多一个数量级。用富含LA的HL60细胞和Jurkat细胞也观察到类似的吞噬刺激作用，而星形胶质细胞触发了Jurkat细胞凋亡。这是由于凋亡的LA补充细胞（而非幼稚细胞）表面存在PSox。这种吞噬作用的增强取决于内在凋亡途径的激活，因为在用Fas抗体攻击的富含LA的细胞中未发生吞噬作用的刺激。凋亡细胞与脂蛋白相关的磷脂酶A2（Lp-PLA2）孵育，这是一种对PSox具有高度特异性的分泌酶，水解了LA补充细胞中的过氧化PS物种，从而将吞噬作用抑制到了幼稚细胞所观察到的水平。 Lp-PLA2对吞噬作用的这种抑制作用被Lp-PLA2的选择性抑制剂SB-435495阻断。筛选可能的受体候选物揭示了几种PS受体和桥接蛋白识别PS和PSox的能力，尽管具有不同的选择性。我们得出的结论是，PSox是一种有效的吞噬“吞噬”信号，它参与了经历内在凋亡的细胞的吞噬。

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