Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation
Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation
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DOI：
10.1074/jbc.m804617200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Gessner, J. Engelbert
中科院分区：
文献类型：
--
作者：
Konrad, Stephanie;Ali, Syed R.;Gessner, J. Engelbert
Fc gamma receptors (Fc gamma R) and the C5a receptor (C5aR) are key effectors of the acute inflammatory response to IgG immune complexes (IC). Their coordinated activation is critical in IC-induced diseases, although the significance of combined signaling by these two different receptor classes in tissue injury is unclear. Here we used the mouse model of the passive reverse lung Arthus reaction to define their requirements for distinct phosphoinositide 3-kinase (PI3K) activities in vivo. We show that genetic deletion of class IB PI3K gamma abrogates C5aR signaling that is crucial for Fc gamma R-mediated activation of lung macrophages. Thus, in PI3K gamma(-/-) mice, IgG IC-induced Fc gamma R regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3K gamma(-/-) mice but was impaired in PI3K gamma(-/-) mice. Consequently, class IA PI3K delta deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3K gamma and PI3K delta coordinate the inflammatory effects of C5aR and Fc gamma R and define PI3K delta as a novel and essential element of Fc gamma R signaling in the generation of C5a in IC disease.
