PI3Kβ plays a critical role in neutrophil activation by immune complexes

Suhasini Kulkarni, Cassian Sitaru, Zoltan Jakus, Karen E. Anderson, George Damoulakis, Keith Davidson, Misa Hirose, Jatinder Juss, David Oxley, Tamara A.M. Chessa, Faruk Ramadani, Herve Guillou, Anne Segonds-Pichon, Anja Fritsch, Gavin E. Jarvis, Klaus Okkenhaug, Ralf Ludwig, Detlef Zillikens, Attila Mocsai, Bart VanhaesebroeckLen R. Stephens, Phillip T. Hawkins

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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 (PI3KβcγR- 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 PI3KβI3Kδ, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3Kβmune 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.

Original languageEnglish
Article numberra23
JournalScience Signaling
Volume4
Issue number168
DOIs
Publication statusPublished - Apr 12 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kulkarni, S., Sitaru, C., Jakus, Z., Anderson, K. E., Damoulakis, G., Davidson, K., Hirose, M., Juss, J., Oxley, D., Chessa, T. A. M., Ramadani, F., Guillou, H., Segonds-Pichon, A., Fritsch, A., Jarvis, G. E., Okkenhaug, K., Ludwig, R., Zillikens, D., Mocsai, A., ... Hawkins, P. T. (2011). PI3Kβ plays a critical role in neutrophil activation by immune complexes. Science Signaling, 4(168), [ra23]. https://doi.org/10.1126/scisignal.2001617