Non-canonical PI3K–Cdc42–Pak–Mek-Erk Signaling Promotes Immune-Complex-Induced Apoptosis in Human Neutrophils

Julia Y. Chu, Ian Dransfield, Adriano G. Rossi, Sonja Vermeren

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)374-386
Number of pages13
JournalCell Reports
Volume17
Issue number2
DOIs
Publication statusPublished - 4 Oct 2016

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