title: Phosphoinositide 3-kinases gamma and delta, linkers of coordinate C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation.
abstract: Fcgamma receptors (FcgammaR) 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 PI3Kgamma abrogates C5aR signaling that is crucial for FcgammaR-mediated activation of lung macrophages. Thus, in PI3Kgamma(-/-) mice, IgG IC-induced FcgammaR regulation, cytokine release, and neutrophil recruitment were blunted. Notably, however, C5a production occurred normally in PI3Kgamma(-/-) mice but was impaired in PI3Kdelta(-/-) mice. Consequently, class IA PI3Kdelta deficiency caused resistance to acute IC lung injury. These results demonstrate that PI3Kgamma and PI3Kdelta coordinate the inflammatory effects of C5aR and FcgammaR and define PI3Kdelta as a novel and essential element of FcgammaR signaling in the generation of C5a in IC disease.
authors.affiliation: Molecular Immunology Research Unit, Clinic for Immunology and Rheumatology, Hanover Medical School, Hanover, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Konrad
authors.forename: Syed R
authors.initials: SR
authors.lastname: Ali
authors.forename: Kristina
authors.initials: K
authors.lastname: Wiege
authors.forename: Shahzad N
authors.initials: SN
authors.lastname: Syed
authors.forename: Linda
authors.initials: L
authors.lastname: Engling
authors.forename: Roland P
authors.initials: RP
authors.lastname: Piekorz
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.forename: Reinhold E
authors.initials: RE
authors.lastname: Schmidt
authors.forename: J Engelbert
authors.initials: JE
authors.lastname: Gessner
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001183:Arthus Reaction / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D007074:Immunoglobulin G; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D044087:Receptor, Anaphylatoxin C5a; D017452:Receptors, IgG; C421683:Pik3cd protein, mouse; C546764:Pik3cg protein, mouse
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