Platelet PI3K Modulates Innate Leukocyte Extravasation during Acid-Induced Acute Lung InflammationFunding Financial support was provided by grants of the Austrian Science Fond (FWF) to A.A. and G.S. (P24978, SFB F54) and of the Austrian National Bank to A.A. (OeNB grant 15961). The authors declare no competing financial interests.
18 January 2019
12 June 2019
01 August 2019 (online)
Introduction Blood platelets are increasingly recognized as modulators of leukocyte effector functions in various pathologies including acute lung injury (ALI). ALI is a life-threatening disease, caused by damage to the alveolar epi- and endothelium. Excessive accumulation of leukocytes leads to severe lung inflammation, resulting in impaired lung function and hypoxemia.
Objective Since leukocyte migration is modulated by activated platelets and phosphatidylinositol 3-kinase (PI3K) signaling is involved in platelet function, we aimed to elucidate the effect of PI3K on platelet-mediated immune responses.
Materials and Methods We generated a mouse model with a platelet-specific deletion of p85α, the most important regulatory subunit of the class IA PI3K, and evaluated platelet function and platelet–leukocyte interactions. Moreover, we analyzed the impact of platelet-specific p85α gene deficiency during sterile peritonitis and acid-induced ALI.
Results In vitro analyses of platelets revealed that lack of p85α led to decreased downstream signaling and diminished expression of surface activation markers, for example, CD62P and CD63, as well as reduced platelet aggregation. Moreover, platelet PI3K essentially mediated direct interactions of platelets with monocytes and neutrophils. In mice, platelet-specific p85α deficiency prevented leukocyte infiltration into the peritoneum and the bronchoalveolar compartment during sterile peritonitis and ALI, respectively. Additionally, the release of the inflammatory cytokine interleukin-12/23 was diminished in platelet p85α-deficient mice during ALI. In contrast to PI3K, neither overexpression nor depletion of platelet phosphatase and tensin homolog, the endogenous antagonist of PI3K, significantly modulated platelet function.
Conclusion Our data indicate a crucial role of platelet PI3K signaling for leukocyte extravasation upon inflammatory stimuli in various diseases models.
Experiments performed by J.B.K.P., W.C.S., M.S., M.M., S.H., G.J.S., B.M., B.B., and H.P.; data analyzed and evaluated by J.B.K.P., W.C.S., M.S., and M.M.; data interpreted by J.B.K.P., W.C.S., M.Z., A.A., and G.S.; study designed by J.B.K.P., W.C.S., A.A., G.S., and S.K.; figures compiled by J.B.K.P., W.C.S., M.S., and A.A.; manuscript written by J.B.K.P., W.C.S., and A.A.; study coordinated and funding acquired by A.A. and G.S. All authors read and approved the final version of the manuscript.
* Both the authors contributed equally to the study.
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