Class IA phosphoinositide 3-kinase β and δ regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae

Keith B. Boyle, David Gyori, Anca Sindrilaru, Karin Scharffetter-Kochanek, Philip R. Taylor, A. Mócsai, Len R. Stephens, Phillip T. Hawkins

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

An effective immune response to the ubiquitous fungus Aspergillus fumigatus is dependent upon production of reactive oxygen species (ROS) by the NADPH oxidase. This is evidenced by the acute sensitivity of oxidase-deficient humans and mice to invasive aspergillosis. Neutrophils are recruited to the lungs shortly postinfection and respond by phagocytosing conidia and mediating extracellular killing of germinated hyphae in a ROS-dependent manner. However, the signaling mechanisms regulating the generation of ROS in response to hyphae are poorly understood. PI3Ks are important regulators of numerous cellular processes, with much recent work describing unique roles for the different class I PI3K isoforms. We showed by live-cell imaging that the lipid products of class I PI3Ks accumulated at the hyphal-bound neutrophil plasma membrane. Further, we used pharmacological and genetic approaches to demonstrate essential, but overlapping, roles for PI3Kβand PI3Kδ in the ROS and spreading responses of murine neutrophils to Aspergillus hyphae. Hyphal-induced ROS responses were substantially inhibited by deletion of the common β2-integrin subunit CD18, with only a minor, redundant role for Dectin-1. However, addition of soluble algal glucans plus the genetic deletion of CD18 were required to significantly inhibit activation of the PI3K-effector protein kinase B. Hyphal ROS responses were also totally dependent on the presence of Syk, but not its ITAM-containing adaptor proteins FcRγ or DAP12, and the Vav family of Rac-guanine nucleotide exchange factors. These results start to define the signaling network controlling neutrophil ROS responses to A. fumigatus hyphae. Copyright

Original languageEnglish
Pages (from-to)2978-2989
Number of pages12
JournalJournal of Immunology
Volume186
Issue number5
DOIs
Publication statusPublished - Mar 1 2011

Fingerprint

Neutrophil Activation
Aspergillus fumigatus
1-Phosphatidylinositol 4-Kinase
Hyphae
Reactive Oxygen Species
Oxidoreductases
Phosphatidylinositol 3-Kinases
Neutrophils
Guanine Nucleotide Exchange Factors
Proto-Oncogene Proteins c-akt
Aspergillosis
Fungal Spores
Glucans
NADPH Oxidase
Aspergillus
IA 3
Phagocytosis
Integrins
Protein Isoforms
Fungi

ASJC Scopus subject areas

  • Immunology

Cite this

Class IA phosphoinositide 3-kinase β and δ regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae. / Boyle, Keith B.; Gyori, David; Sindrilaru, Anca; Scharffetter-Kochanek, Karin; Taylor, Philip R.; Mócsai, A.; Stephens, Len R.; Hawkins, Phillip T.

In: Journal of Immunology, Vol. 186, No. 5, 01.03.2011, p. 2978-2989.

Research output: Contribution to journalArticle

Boyle, KB, Gyori, D, Sindrilaru, A, Scharffetter-Kochanek, K, Taylor, PR, Mócsai, A, Stephens, LR & Hawkins, PT 2011, 'Class IA phosphoinositide 3-kinase β and δ regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae', Journal of Immunology, vol. 186, no. 5, pp. 2978-2989. https://doi.org/10.4049/jimmunol.1002268
Boyle, Keith B. ; Gyori, David ; Sindrilaru, Anca ; Scharffetter-Kochanek, Karin ; Taylor, Philip R. ; Mócsai, A. ; Stephens, Len R. ; Hawkins, Phillip T. / Class IA phosphoinositide 3-kinase β and δ regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae. In: Journal of Immunology. 2011 ; Vol. 186, No. 5. pp. 2978-2989.
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AU - Taylor, Philip R.

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