title: Non-canonical PI3K-Cdc42-Pak-Mek-Erk Signaling Promotes Immune-Complex-Induced Apoptosis in Human Neutrophils.
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.
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Chu
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Dransfield
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Adriano G
authors.initials: AG
authors.lastname: Rossi
authors.affiliation: The MRC Centre for Inflammation Research, Queen's Medical Research Institute, 47 Little France Crescent, University of Edinburgh, Edinburgh EH16 4TJ, UK. Electronic address: sonja.vermeren@ed.ac.uk.
authors.forename: Sonja
authors.initials: S
authors.lastname: Vermeren
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics*; D003598:Cytoskeletal Proteins; D053492:Elafin / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018375:Neutrophil Activation / Q000235:genetics* / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics; D015398:Signal Transduction; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism; D020741:rho GTP-Binding Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000936:Antigen-Antibody Complex; D003598:Cytoskeletal Proteins; D053492:Elafin; C489017:FCGR1A protein, human; C506806:PI3 protein, human; D017452:Receptors, IgG; C075598:CDC42EP1 protein, human; D054462:p21-Activated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020930:MAP Kinase Kinase Kinases; D020741:rho GTP-Binding Proteins