Phosphoinositide 3-kinases gamma and delta, linkers of coordinate C5a receptor-Fcgamma receptor activation and immune complex-induced inflammation.
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.
Konrad
Stephanie
S
Molecular Immunology Research Unit, Clinic for Immunology and Rheumatology, Hanover Medical School, Hanover, Germany.
Ali
Syed R
SR
Wiege
Kristina
K
Syed
Shahzad N
SN
Engling
Linda
L
Piekorz
Roland P
RP
Hirsch
Emilio
E
Nürnberg
Bernd
B
Schmidt
Reinhold E
RE
Gessner
J Engelbert
JE
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
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
J Biol Chem. 2007 Dec 28;282(52):37906-12
17956862
EMBO J. 2004 Sep 1;23(17):3505-15
15318168
Eur J Immunol. 2005 Apr;35(4):1283-91
15739165
Immunity. 2002 Feb;16(2):157-68
11869678
J Clin Invest. 1986 Jun;77(6):1812-6
3711336
Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127-50
9838078
Science. 2000 Feb 11;287(5455):1049-53
10669418
Immunology. 2007 Aug;121(4):448-61
17614878
J Clin Invest. 2006 Feb;116(2):512-20
16453025
Immunity. 2002 Mar;16(3):441-51
11911828
J Clin Invest. 2002 Dec;110(12):1823-30
12488432
Science. 2000 Feb 11;287(5455):1046-9
10669417
Annu Rev Biochem. 1998;67:481-507
9759495
Blood. 2007 Nov 1;110(9):3202-8
17644738
J Immunol. 2007 Feb 15;178(4):2328-35
17277138
Science. 1999 Jan 15;283(5400):393-7
9888855
J Exp Med. 2002 Sep 16;196(6):753-63
12235209
Blood. 2005 Jul 1;106(1):110-7
15705797
Nat Rev Immunol. 2002 Aug;2(8):580-92
12154377
Nat Immunol. 2003 Apr;4(4):313-9
12660731
Thromb Haemost. 2008 Feb;99(2):279-85
18278175
Annu Rev Immunol. 1999;17:931-72
10358778
Mol Cell Biol. 2002 Dec;22(24):8580-91
12446777
Science. 1999 Jan 15;283(5400):390-2
9888854
J Exp Med. 1997 Aug 29;186(5):749-56
9271590
J Biol Chem. 2002 Jul 26;277(30):27535-44
11983693
Br J Pharmacol. 2007 Oct;152(4):429-48
17603557
Semin Immunol. 2002 Feb;14(1):7-18
11884226
J Immunol. 2001 Apr 15;166(8):5193-200
11290803
Science. 2000 Feb 11;287(5455):1040-6
10669416
Eur J Immunol. 2007 Feb;37(2):416-24
17236236
Nat Rev Immunol. 2007 Mar;7(3):191-201
17290298
Nature. 2004 Oct 21;431(7011):1007-11
15496927
Biochem Soc Trans. 2003 Feb;31(Pt 1):270-4
12546700
J Immunol. 2007 Dec 15;179(12):8350-6
18056380
Circulation. 1998 Jun 9;97(22):2259-67
9631876
Biochim Biophys Acta. 2008 Jan;1784(1):159-85
17997386
Annu Rev Cell Dev Biol. 2001;17:615-75
11687500
Immunol Lett. 2005 Aug 15;100(1):56-67
16125792
Eur J Immunol. 2000 Feb;30(2):481-90
10671203
Immunity. 2006 Jan;24(1):19-28
16413920
Eur J Immunol. 2008 May;38(5):1215-24
18412166
Science. 2002 Aug 9;297(5583):1031-4
12130661
Blood. 2004 May 1;103(9):3448-56
14751923
J Immunol. 2005 Mar 1;174(5):3041-50
15728518
Blood. 2007 Oct 15;110(8):2940-7
17626838
Annu Rev Immunol. 2001;19:275-90
11244038
Nat Med. 2006 Jun;12(6):682-7
16715088
Circulation. 1999 Dec 21-28;100(25):2499-506
10604887