PI3K beta Plays a Critical Role in Neutrophil Activation by Immune Complexes

S. Kulkarni, C. Sitaru, Z. Jakus, K.E. Anderson, G. Damoulakis, K. Davidson, M. Hirose, J. Juss, D. Oxley, T.A.M. Chessa, F. Ramadani, H. Guillou, A. Segonds-Pichon, A. Fritsch, Gavin Jarvis, K. Okkenhaug, R. Ludwig, D. Zillikens, A. Mocsai, B. VanhaesebroeckL.R. Stephens, P.T. Hawkins

Research output: Contribution to journalArticlepeer-review

110 Citations (Scopus)


Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (Fc gamma Rs). Here, we used genetic and pharmacological approaches to define a selective role for the beta isoform of phosphoinositide 3-kinase (PI3K beta) in Fc gamma R-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 PI3K beta 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 PI3K beta and PI3K delta, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3K beta by immune complexes involved cooperation between Fc gamma Rs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B-4. Coincident activation by a tyrosine kinase-coupled receptor (Fc gamma R) and a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (BLT1) may provide a rationale for the preferential activation of the beta isoform of PI3K. PI3K beta-deficient mice were highly protected in an Fc gamma R-dependent model of autoantibody-induced skin blistering and were partially protected in an Fc gamma R-dependent model of inflammatory arthritis, whereas combined deficiency of PI3K beta and PI3K delta resulted in near-complete protection in the latter case. These results define PI3K beta as a potential therapeutic target in inflammatory disease.
Original languageEnglish
Article numberra23
JournalScience Signaling
Issue number168
Publication statusPublished - 12 Apr 2011

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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