alpha(9)beta(1) integrin engagement inhibits neutrophil spontaneous apoptosis: involvement of Bcl-2 family members.
alpha(9)beta(1) integrin engagement inhibits neutrophil spontaneous apoptosis: involvement of Bcl-2 family members.
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DOI：
10.1016/j.bbamcr.2010.03.012
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发表时间：
2010-07
期刊：
影响因子：
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通讯作者：
R. Saldanha-Gama;J. Moraes;Andréa Mariano-Oliveira;A. L. Coelho;E. Walsh;C. Marcinkiewicz;C. Barja-Fidalgo
中科院分区：
文献类型：
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作者：
R. Saldanha-Gama;J. Moraes;Andréa Mariano-Oliveira;A. L. Coelho;E. Walsh;C. Marcinkiewicz;C. Barja-Fidalgo
整合素信号传导由通常与细胞存活相关的特征明确的途径组成。 α9β1整合素最近已成为研究目标，并已被证明对中性粒细胞具有促生存作用。然而，目前还没有关于α9β1整合素偶联信号通路如何相互作用以及它们如何汇聚最终调节中性粒细胞自发凋亡的详细研究。在这方面，我们试图研究α9β1整合素参与触发的主要信号传导事件以及这些信号传导途径如何调节人类中性粒细胞的凋亡程序。使用 VLO5（一种蛇毒解整合素，它与中性粒细胞中的 α9β1 整合素结合），我们证明 α9β1 整合素的结合会导致整合素信号通路的激活，并有效减少中性粒细胞自发凋亡。这些作用依赖于 PI3K 和 MAPK 通路的激活，因为 LY294002（PI3K 抑制剂）或 PD95059（MEK 抑制剂）均可恢复 VLO5/α9β1 相互作用的作用。此外，我们还发现，VLO5/α9β1 接合可诱导 NF-κB 核易位，并通过诱导促凋亡蛋白 Bad 降解和增加抗凋亡蛋白 Bcl-xL 的表达来增加抗凋亡蛋白与促凋亡蛋白之间的比例。 VLO5 还通过阻止 Bax 易位至线粒体外膜以及随后的细胞色素 c 释放来抑制中性粒细胞自发凋亡的早期步骤。总之，随着人类中性粒细胞中α9β1整合素信号通路的机制细节变得更加清晰，开发新的治疗剂来治疗中性粒细胞发挥重要作用的人类疾病应该成为可能。
Integrin signaling is comprised of well-characterized pathways generally involved in cell survival. α9β1integrin has recently become a target of study and has been shown to present pro-survival effects on neutrophils. However, there are no detailed studies on how α9β1integrin-coupled signaling pathways interact and how they converge to finally modulate spontaneous apoptosis in neutrophils. In this regard we sought to investigate the main signaling events triggered by α9β1integrin engagement and how these signaling pathways modulate the apoptotic program of human neutrophils. Using VLO5, a snake venom disintegrin shown to bind to α9β1integrin in neutrophils, we demonstrate that α9β1integrin engagement leads to the activation of integrin signaling pathways and potently reduces neutrophil spontaneous apoptosis. These effects are dependent on the activation of PI3K and MAPK pathways, since both LY294002 (PI3K inhibitor) or PD95059 (MEK inhibitor) reverted the effects of VLO5/α9β1interaction. Moreover we show that VLO5/α9β1engagement induces NF-κB nuclear translocation and increases the ratio between anti- and pro-apoptotic proteins by inducing the degradation of pro-apoptotic protein Bad and increasing the expression of anti-apoptotic protein Bcl-xL. VLO5 also inhibited the early steps of neutrophil spontaneous apoptosis by preventing Bax translocation to the outer mitochondrial membrane and consequent cytochrome c release. In conclusion, as the mechanistic details of α9β1integrin signaling pathways in human neutrophils becomes clearer, it should become possible to develop new therapeutic agents for human diseases where neutrophils play a prominent role.