Critical role for PI3Kγ-dependent neutrophil reactive oxygen species in WKYMVm-induced microvascular hyperpermeability.

PI3K has been indicated in regulating microvascular permeability changes during inflammation. However, its role in neutrophil-driven microvascular leakage in acute inflammation remains unclear. Using intravital microscopy in mice, we examined the role of PI3Kγ and PI3Kδ in formyl peptide WKYMVm- and chemokine CXCL2-induced permeability changes and assessed simultaneously neutrophil adhesion and emigration in post-capillary venules of murine cremaster muscle. We found a PI3Kγ-specific mechanism in WKYMVm-induced but not CXCL2-induced microvascular hyperpermeability. The increased microvascular permeability triggered by WKYMVm was not entirely due to neutrophil adhesion and emigration in cremasteric microvasculature in different PI3K transgenic mouse strains. The PI3Kγ-specific hyperpermeability was neutrophil-mediated as this was reduced after depletion of neutrophils in mouse circulation. Chimeric mice with PI3Kγ-deficient neutrophils but wild-type endothelium also showed reduced hyperpermeability. Furthermore, we found that the catalytic function of PI3Kγ was required for reactive oxygen species generation in neutrophils stimulated with WKYMVm. Pharmacological scavenging PI3Kγ-dependent in the tissue eliminated the discrepancy in hyperpermeability between different PI3K transgenic mice and alleviated WKYMVm-induced microvascular leakage in all mouse strains tested. In conclusion, our study uncovers the critical role for PI3Kγ-dependent duanyu1670 generation by neutrophils in formyl peptide-induced microvascular hyperpermeability during neutrophil recruitment.

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