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.

Class-IA Phosphoinositide 3-Kinase p110^|^beta; Triggers GPCR-Induced Superoxide Production in p110^|^gamma;-Deficient Murine Neutrophils

“…An alternative explanation is that an effective agonist or the priming process is necessary to produce tyrosine-phosphorylated proteins, which have been reported to augment the action of Gβγ on p110β (37,38). A recent study has shown that p110β plays a critical role in leukotriene B 4 (a GPCR agonist)-induced superoxide production by IgG-activated neutrophils (39). The fact may also be explained by the latter explanation indicating the interaction between GPCR and tyrosine kinase-coupled receptors.…”

Novel Phosphoinositide 3-Kinaseδ,γInhibitor: Potent Anti-Inflammatory Effects and Joint Protection in Models of Rheumatoid Arthritis

“…IPI-145 is much less active against PI3Ka and has a modest effect on PI3Kb. Although the role of PI3Kb is uncertain due to embryonic lethality in knockout mice, some data suggest that it can regulate neutrophil function (Kulkarni et al, 2011). Nevertheless, it is more likely that the pharmacologic activity observed in AA and CIA models is primarily due to an action on d and g isoforms.…”

Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies

“…However, neutrophils from mice lacking PI3K␤ and expressing kinase-dead PI3K␦ D910A displayed a marked reduction in neutrophil ROS generation. The importance of PI3K␤ and its cooperation with PI3K␦ was further underlined by a study from the same group that demonstrated PI3K␤ plays an essential, nonredundant role in the efficient activation of mouse neutrophils by IgG-containing immune complexes (Kulkarni et al, 2011). Neutrophils detect these immune complexes through Fc receptors for IgG (Fc␥Rs).…”