Phosphoinositide 3-kinase gamma: a key modulator in inflammation and allergy.
Chronic inflammation and allergy involve the activation of tissue-resident cells and, later on, the invasion of effector cells. We have previously shown that the loss of phosphoinositide 3-kinase (PI3K) gamma impairs chemokine-dependent migration of neutrophils and macrophages both in vitro and in vivo. On the other hand, PI3K gamma is not required either during phagocytic processes or in the activation of bactericidal activities like granule secretion and particle-mediated respiratory burst in neutrophils. Tissue mast cells are key regulators in allergy and inflammation and release histamine upon clustering of their IgE receptors. We have demonstrated that murine mast cell responses are exacerbated in vitro and in vivo by autocrine signals, and require functional PI3K gamma. Adenosine, acting through the A(3) adenosine receptor, as well as other agonists of G(alpha i)-coupled receptors, transiently increased PtdIns(3,4,5) P (3) exclusively via PI3K gamma. PI3K gamma-derived PtdIns(3,4,5) P (3) was instrumental for initiation of a sustained influx of external Ca(2+) and degranulation. Mice that lacked PI3K gamma did not form oedema when challenged by passive systemic anaphylaxis. PI3K gamma thus relays inflammatory signals through various GPCRs, and is thus central to mast cell function. Taken together, this suggests that pharmaceutical targeting of PI3K gamma might alleviate inflammation at both early and late stages of the allergic response.
Wymann
M P
MP
Department of Medicine, University of Fribourg, Rue du Musée 5, CH-1700 Fribourg, Switzerland. Matthias.Wymann@UniFR.ch
Björklöf
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K
Calvez
R
R
Finan
P
P
Thomast
M
M
Trifilieff
A
A
Barbier
M
M
Altruda
F
F
Hirsch
E
E
Laffargue
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement; D058544:Class Ib Phosphatidylinositol 3-Kinase; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism*; D007073:Immunoglobulin E / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*
D007527:Isoenzymes; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D002118:Calcium