title: PI3Kβ plays a critical role in neutrophil activation by immune complexes.
abstract: Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (FcγRs). Here, we used genetic and pharmacological approaches to define a selective role for the β isoform of phosphoinositide 3-kinase (PI3Kβ) in FcγR-dependent activation of mouse neutrophils by immune complexes of IgG and antigen immobilized on a plate surface. At low concentrations of immune complexes, loss of PI3Kβ alone substantially inhibited the production of reactive oxygen species (ROS) by neutrophils, whereas at higher doses, similar suppression of ROS production was achieved only by targeting both PI3Kβ and PI3Kδ, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3Kβ by immune complexes involved cooperation between FcγRs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B₄. Coincident activation by a tyrosine kinase-coupled receptor (FcγR) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the β isoform of PI3K. PI3Kβ-deficient mice were highly protected in an FcγR-dependent model of autoantibody-induced skin blistering and were partially protected in an FcγR-dependent model of inflammatory arthritis, whereas combined deficiency of PI3Kβ and PI3Kδ resulted in near-complete protection in the latter case. These results define PI3Kβ as a potential therapeutic target in inflammatory disease.
authors.affiliation: Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Suhasini
authors.initials: S
authors.lastname: Kulkarni
authors.forename: Cassian
authors.initials: C
authors.lastname: Sitaru
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Jakus
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.forename: George
authors.initials: G
authors.lastname: Damoulakis
authors.forename: Keith
authors.initials: K
authors.lastname: Davidson
authors.forename: Misa
authors.initials: M
authors.lastname: Hirose
authors.forename: Jatinder
authors.initials: J
authors.lastname: Juss
authors.forename: David
authors.initials: D
authors.lastname: Oxley
authors.forename: Tamara A M
authors.initials: TA
authors.lastname: Chessa
authors.forename: Faruk
authors.initials: F
authors.lastname: Ramadani
authors.forename: Herve
authors.initials: H
authors.lastname: Guillou
authors.forename: Anne
authors.initials: A
authors.lastname: Segonds-Pichon
authors.forename: Anja
authors.initials: A
authors.lastname: Fritsch
authors.forename: Gavin E
authors.initials: GE
authors.lastname: Jarvis
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Ralf
authors.initials: R
authors.lastname: Ludwig
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.forename: Attila
authors.initials: A
authors.lastname: Mocsai
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Len R
authors.initials: LR
authors.lastname: Stephens
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D018801:CD2 Antigens / Q000235:genetics / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000378:metabolism; D007133:Immunoglobulin Joining Region / Q000235:genetics / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000378:metabolism; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018375:Neutrophil Activation / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D018801:CD2 Antigens; D004791:Enzyme Inhibitors; D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; C503704:Ltb4r1 protein, mouse; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017382:Reactive Oxygen Species; D017452:Receptors, IgG; D018102:Receptors, Leukotriene B4; D058543:Class Ia Phosphatidylinositol 3-Kinase