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

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. [Display omitted] •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.