Phosphoinositide 3-Kinases γ and δ, Linkers of Coordinate C5a Receptor-Fcγ Receptor Activation and Immune Complex-induced Inflammation

Abstract

Fc␥ receptors (Fc␥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 ICinduced 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␥ abrogates C5aR signaling that is crucial for Fc␥R-mediated activation of lung macrophages. Thus, in PI3K␥ ؊/؊ mice, IgG IC-induced Fc␥R regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3K␥ ؊/؊ mice but was impaired in PI3K␦ ؊/؊ mice. Consequently, class IA PI3K␦ deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3K␥ and PI3K␦ coordinate the inflammatory effects of C5aR and Fc␥R and define PI3K␦ as a novel and essential element of Fc␥R signaling in the generation of C5a in IC disease.

Both FcγRIV and FcγRIII are essential receptors mediating type II and type III autoimmune responses via FcRγ‐LAT‐dependent generation of C5a

“…6D) similar to that found in FcRg-chain-deficient mice, supporting the concept that coordinated C5aR and FcgR activation is a crucial regulatory event in the initiation of certain type II and III autoimmune responses [31,41]. As recently reported, C5aR mediates an inverse regulation of FcgR (through induction of FcgRIII and suppression of FcgRII) by a pertussis toxin-sensitive pathway that depends on the presence of Gai2 [16] and PI3Kg [36] signaling molecules both in vitro and in vivo. On the other hand, FcRg-chain-mediated signaling is critical for the generation of C5a [28,41].…”

“…Further analysis with the now available FcgRIII-and FcgRIV-blocking Ab will provide a better understanding of the overlapping versus alternative roles of these two activating FcgR in relation to C5a and C5aR in distinct IgG-mediated pathologies. Clearly, further studies on the signaling molecules of the coordinate FcgR and C5aR activation, such as trimeric G-proteins [16], PI3-kinases [36], calciumregulatory proteins [42], and adaptor molecules (this report) in relation to the pathogenic effects of self-reactive Ab would help establish new strategies for the development of therapeutics in immunological diseases.…”

“…PI3Kd-deficient mice display an impaired generation of AM cell-derived C5a that is critical for coordinate FcgR and C5aR activation and subsequent production of cytokines and chemokines [36]. To examine the relevance of FcgRIII and FcgRIV for C5a production, IC-challenged B6 mice were treated with the FcgRIII-and FcgRIVblocking mAb, killed at early time points (5 h), and BALF were assayed for C5a bioactivity as described [15,16].…”

Gαi2 Is the Essential Gαi Protein in Immune Complex–Induced Lung Disease

“…The C5aR-FcgR interaction is mediated by a PTxsensitive pathway (28) and was previously shown to depend on the presence of the G i -protein-regulated PI3Kg (11). However, the cellular origin of the PI3Kg-mediated effects was not defined.…”

“…Both C5aR and chemokine receptors belong to the family of G-protein-coupled receptors (GPCRs), mediating their functions primarily through heterotrimeric G i proteins. Accordingly, receptor activation leads to dissociation of the Ga subunit from the Gbg dimer and subsequent activation of intracellular effectors, such as PI3Kg, a previously demonstrated integral component of the C5aR-G i -triggered signaling cascade in neutrophil IC inflammation (11).…”