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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigen-Antibody Complex / genetics
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Antigen-Antibody Complex / immunology
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Antigen-Antibody Complex / metabolism*
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Arthus Reaction / enzymology*
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Arthus Reaction / genetics
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Arthus Reaction / immunology
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Class I Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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Disease Models, Animal
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Immunoglobulin G / genetics
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Immunoglobulin G / immunology
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Immunoglobulin G / metabolism
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Inflammation / enzymology
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Inflammation / genetics
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Inflammation / immunology
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Isoenzymes / genetics
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Isoenzymes / immunology
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Isoenzymes / metabolism
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Mice
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Mice, Knockout
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / immunology
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Phosphatidylinositol 3-Kinases / metabolism*
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Receptor, Anaphylatoxin C5a / genetics
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Receptor, Anaphylatoxin C5a / immunology
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Receptor, Anaphylatoxin C5a / metabolism*
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Receptors, IgG / genetics
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Receptors, IgG / immunology
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Receptors, IgG / metabolism*
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Signal Transduction / genetics
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Signal Transduction / immunology
Substances
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Antigen-Antibody Complex
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Immunoglobulin G
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Isoenzymes
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Receptor, Anaphylatoxin C5a
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Receptors, IgG
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Class I Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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Pik3cd protein, mouse
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Pik3cg protein, mouse