Non-canonical PI3K-Cdc42-Pak-Mek-Erk Signaling Promotes Immune-Complex-Induced Apoptosis in Human Neutrophils.
Non-canonical PI3K-Cdc42-Pak-Mek-Erk Signaling Promotes Immune-Complex-Induced Apoptosis in Human Neutrophils.
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DOI：
10.1016/j.celrep.2016.09.006
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发表时间：
2016-10-04
期刊：
影响因子：
8.8
通讯作者：
Vermeren S
中科院分区：
文献类型：
--
作者：
Chu JY;Dransfield I;Rossi AG;Vermeren S
中性粒细胞是外周血白细胞，代表了免疫细胞防御细菌和真菌感染的第一道防线，但在炎症反应的产生中也是至关重要的参与者。许多中性粒细胞表面受体通过激活激动剂激活的pi3k来调节重要的细胞过程。我们在这里表明，人类中性粒细胞与不溶性免疫复合物的激活驱动了一个以前未被表征的，pi3k依赖的，非规范的促凋亡信号通路，FcγR-PI3Kβ/δ-Cdc42-Pak-Mek-Erk。这是罕见的Ras/ raf独立的Erk激活和pi3k介导的Cdc42激活的证明。此外，免疫复合物和fmlf诱导的信号传导的比较分析揭示了人和小鼠中性粒细胞使用的通路的关键差异。我们在本研究中确定的非规范途径可能对依赖免疫复合物驱动的中性粒细胞激活的慢性炎症性疾病的炎症解决很重要。免疫复合物激活的人中性粒细胞使用PI3Kβ/δ-Cdc42-Pak-Mek-Erk信号通路免疫复合物诱导的非典型中性粒细胞信号通路是促凋亡的其他免疫复合物诱导的中性粒细胞功能依赖于其他PI3K效应物免疫复合物诱导的PI3K信号通路在人和小鼠之间不保守，PI3K信号通路失调与许多疾病过程相关。Chu等人现在发现一种非常规的信号通路PI3Kβ/δ-Cdc42-Pak-Mek-Erk调节免疫复合物诱导的人中性粒细胞凋亡。这种在小鼠中不保守的非规范PI3K信号通路可能影响人类炎症的消退。
Neutrophils are peripheral blood leukocytes that represent the first line of immune cell defense against bacterial and fungal infections but are also crucial players in the generation of the inflammatory response. Many neutrophil cell surface receptors regulate important cellular processes via activation of agonist-activated PI3Ks. We show here that activation of human neutrophils with insoluble immune complexes drives a previously uncharacterized, PI3K-dependent, non-canonical, pro-apoptotic signaling pathway, FcγR-PI3Kβ/δ-Cdc42-Pak-Mek-Erk. This is a rare demonstration of Ras/Raf-independent activation of Erk and of PI3K-mediated activation of Cdc42. In addition, comparative analysis of immune-complex- and fMLF-induced signaling uncovers key differences in pathways used by human and murine neutrophils. The non-canonical pathway we identify in this study may be important for the resolution of inflammation in chronic inflammatory diseases that rely on immune-complex-driven neutrophil activation. Immune-complex-activated human neutrophils use PI3Kβ/δ-Cdc42-Pak-Mek-Erk signaling Immune-complex-induced non-canonical neutrophil signaling is pro-apoptotic Other immune-complex-induced neutrophil functions depend on alternative PI3K effectors Immune-complex-induced PI3K signaling is not conserved between humans and mice Dysregulated PI3K signaling is associated with many disease processes. Chu et al. now find that an unconventional signaling pathway, PI3Kβ/δ-Cdc42-Pak-Mek-Erk, regulates immune-complex-induced apoptosis in human neutrophils. This non-canonical PI3K signaling pathway, which is not conserved in the mouse, may affect the resolution of inflammation in humans.
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影响因子：
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