Fcγ receptors (FcγR) 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 PI3Kγ abrogates C5aR signaling that is crucial for FcγR-mediated activation of lung macrophages. Thus, in PI3Kγ-/- mice, IgG IC-induced FcγR regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3Kγ-/- mice but was impaired in PI3Kδ-/- mice. Consequently, class IA PI3Kδ deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3Kγ and PI3Kδ coordinate the inflammatory effects of C5aR and FcγR and define PI3Kδ as a novel and essential element of FcγR signaling in the generation of C5a in IC disease
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