| First Author | Kulkarni S | Year | 2011 |
| Journal | Sci Signal | Volume | 4 |
| Issue | 168 | Pages | ra23 |
| PubMed ID | 21487106 | Mgi Jnum | J:185999 |
| Mgi Id | MGI:5430716 | Doi | 10.1126/scisignal.2001617 |
| Citation | Kulkarni S, et al. (2011) PI3Kbeta plays a critical role in neutrophil activation by immune complexes. Sci Signal 4(168):ra23 |
| abstractText | Neutrophils are activated by immunoglobulin G (IgG)-containing immune complexes through receptors that recognize the Fc portion of IgG (FcgammaRs). Here, we used genetic and pharmacological approaches to define a selective role for the beta isoform of phosphoinositide 3-kinase (PI3Kbeta) in FcgammaR-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 PI3Kbeta 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 PI3Kbeta and PI3Kdelta, suggesting that this pathway displays stimulus strength-dependent redundancy. Activation of PI3Kbeta by immune complexes involved cooperation between FcgammaRs and BLT1, the receptor for the endogenous proinflammatory lipid leukotriene B(4). Coincident activation by a tyrosine kinase-coupled receptor (FcgammaR) 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. PI3Kbeta-deficient mice were highly protected in an FcgammaR-dependent model of autoantibody-induced skin blistering and were partially protected in an FcgammaR-dependent model of inflammatory arthritis, whereas combined deficiency of PI3Kbeta and PI3Kdelta resulted in near-complete protection in the latter case. These results define PI3Kbeta as a potential therapeutic target in inflammatory disease. |
