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Sci. Signal., 12 April 2011
Vol. 4, Issue 168, p. ra23
[DOI: 10.1126/scisignal.2001617]


PI3Kβ Plays a Critical Role in Neutrophil Activation by Immune Complexes

Suhasini Kulkarni1, Cassian Sitaru2,3, Zoltan Jakus4, Karen E. Anderson1, George Damoulakis1, Keith Davidson1, Misa Hirose2, Jatinder Juss1, David Oxley1, Tamara A. M. Chessa1, Faruk Ramadani5, Herve Guillou1, Anne Segonds-Pichon1, Anja Fritsch6, Gavin E. Jarvis7, Klaus Okkenhaug5, Ralf Ludwig2, Detlef Zillikens2, Attila Mocsai4, Bart Vanhaesebroeck8, Len R. Stephens1*{dagger}, and Phillip T. Hawkins1*{dagger}

1 Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK.
2 Department of Dermatology, University of Lübeck, 23538 Lübeck, Germany.
3 Department of Dermatology and Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
4 Department of Physiology, Semmelweis University School of Medicine, P.O. Box 259, 1444 Budapest, Hungary.
5 Laboratory of Lymphocyte Signaling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.
6 Department of Dermatology, University Medical Centre, 79104 Freiburg, Germany.
7 Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
8 Centre for Cell Signaling, Institute of Cancer, Queen Mary University of London, London EC1M 6BQ, UK.

* These authors contributed equally to this work.

Abstract: 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 β isoform of phosphoinositide 3-kinase (PI3Kβ) 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 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 PI3K{delta}, suggesting that this pathway displays stimulus strength–dependent redundancy. Activation of PI3Kβ by immune complexes involved cooperation between Fc{gamma}Rs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B4. 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 β isoform of PI3K. PI3Kβ-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 PI3Kβ and PI3K{delta} resulted in near-complete protection in the latter case. These results define PI3Kβ as a potential therapeutic target in inflammatory disease.

{dagger} To whom correspondence should be addressed. E-mail: phillip.hawkins{at} (P.T.H.); len.stephens{at} (L.R.S.)

Citation: 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, G. E. Jarvis, K. Okkenhaug, R. Ludwig, D. Zillikens, A. Mocsai, B. Vanhaesebroeck, L. R. Stephens, P. T. Hawkins, PI3Kβ Plays a Critical Role in Neutrophil Activation by Immune Complexes. Sci. Signal. 4, ra23 (2011).

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