Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases.
Class I phosphoinositide 3-kinases (PI3K) are known to play a significant role in neutrophil chemotaxis. However, the relative contributions of different PI3K isoforms, and how these impact on lung inflammation, have not been addressed. In vitro studies using wild-type and PI3Kgamma knockout neutrophils demonstrated the major role of the gamma isoform in chemotactic but not chemokinetic events. This was confirmed by a model of direct chemokine instillation into the airways in vivo. Within all studies, a low yet significant degree of neutrophil movement in the absence of PI3Kgamma could be observed. No role for the delta isoform was demonstrated both in vitro and in vivo using PI3Kdelta kinase-dead knock-in mice. Moreover, further studies using the broad-spectrum PI3K inhibitors wortmannin or LY294002 showed no other class I PI3K isoforms to be involved in these chemotactic processes. Here, we identify a contributory PI3K-independent mechanism of neutrophil movement, yet demonstrate PI3Kgamma as the pivotal mediator through which the majority of neutrophils migrate into the lung in response to chemokines. These data resolve the complexities of chemokine-induced neutrophilia and PI3K signaling and define the gamma isoform as a promising target for new therapeutics to treat airway inflammatory diseases.
Thomas
Matthew J
MJ
Novartis Institutes for BioMedical Research, Horsham, UK. matthew.thomas@pharma.novartis.com
Smith
Alexandra
A
Head
Denise H
DH
Milne
Laura
L
Nicholls
Andrew
A
Pearce
Wayne
W
Vanhaesebroeck
Bart
B
Wymann
Matthias P
MP
Hirsch
Emilio
E
Trifilieff
Alexandre
A
Walker
Christoph
C
Finan
Peter
P
Westwick
John
J
D000818:Animals; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000276:immunology; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D012137:Respiratory System / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology
D018925:Chemokines; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases