Essential role of phosphoinositide 3-kinase gamma in eosinophil chemotaxis within acute pulmonary inflammation.
We and others have established an important role for phosphoinositide-3 kinase gamma (PI3Kgamma) in the chemotactic responses of macrophages and neutrophils. The involvement of this lipid kinase in allergic inflammatory responses is, however, yet to be fully determined. Here we compare wild-type (WT) and PI3Kgamma(-/-) (KO) mice within a model of ovalbumin (OVA) -specific pulmonary inflammation. Upon OVA aerosol challenge, cell influx into the bronchoalveolar lavage (BAL) fluid consisted of neutrophils, macrophages and, more significantly, eosinophils - which are key effector cells in allergic inflammation. Each population was reduced by up to 80% in KO mice, demonstrating a role for PI3Kgamma in cell infiltration into the airways. The mechanism of reduced eosinophilia was analysed within both development and effector stages of the immune response. Comparable levels of OVA-specific T-cell proliferation and immunoglobulin production were established in both strains. Furthermore, no significant differences between WT and KO chemokine production were observed. Having identified the critical point of PI3Kgamma involvement, KO eosinophil chemotactic dysfunction was confirmed in vitro. These data are the first to demonstrate the vital role of PI3Kgamma in acute allergic inflammation. The profound dependency of eosinophils on PI3Kgamma for pulmonary influx identifies this lipid kinase as an attractive target for the pharmacological intervention of asthma.
Thomas
Matthew
M
Novartis Institutes for BioMedical Research, Horsham, West Sussex, United Kingdom. matthew.thomas@pharma.novartis.com
Edwards
Matthew J
MJ
Sawicka
Elzbieta
E
Duggan
Nicholas
N
Hirsch
Emilio
E
Wymann
Matthias P
MP
Owen
Charles
C
Trifilieff
Alexandre
A
Walker
Christoph
C
Westwick
John
J
Finan
Peter
P