The regulatory subunits of PI3Kγ control distinct neutrophil responses.

Neutrophils, which migrate toward inflamed sites and kill pathogens by producing reactive oxygen species are important in the defense against bacterial and fungal pathogens, but their inappropriate regulation causes various chronic inflammatory diseases. Phosphoinositide 3-kinase γ (PI3Kγ) functions downstream of proinflammatory G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) in neutrophils and is a therapeutic target. In neutrophils, PI3Kγ consists of a p110γ catalytic subunit, which is activated by the guanosine triphosphatase Ras, and either a p84 or p101 regulatory subunit. Loss or inhibition of p110γ or expression of a Ras-insensitive variant p110γ (p110γ(DASAA/DASAA)) impairs PIP3 production, Akt phosphorylation, migration, and formation in response to GPCR activation. The p101 subunit binds to, and mediates PI3Kγ activation by, G protein βγ subunits, and p101(-/-) neutrophils have a similar phenotype to that of p110γ(-/-) neutrophils, except that duanyu1670 responses are normal. We found that p84(-/-) neutrophils displayed reduced GPCR-stimulated PIP3 and Akt signaling, which was indistinguishable from that of p101(-/-) neutrophils. However, p84(-/-) neutrophils produced less duanyu1670 and exhibited normal migration in response to GPCR stimulation. These data suggest that p84-containing PI3Kγ controls GPCR-dependent duanyu1670 production. Thus, the PI3Kγ regulatory subunits enable PI3Kγ to mediate distinct neutrophil responses, which may occur by targeting PIP3 signaling into spatially distinct domains.

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