Platelet PI3K Modulates Innate Leukocyte Extravasation during Acid-Induced Acute Lung Inflammation

Julia Barbara Kral-Pointner; Waltraud Cornelia Schrottmaier; Manuel Salzmann; Marion Mussbacher; Georg Johannes Schmidt; Bernhard Moser; Stefan Heber; Birgit Birnecker; Hannah Paar; Maria Zellner; Sylvia Knapp; Alice Assinger; Gernot Schabbauer

doi:10.1055/s-0039-1693693

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2019; 119(10): 1642-1654
DOI: 10.1055/s-0039-1693693

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

Platelet PI3K Modulates Innate Leukocyte Extravasation during Acid-Induced Acute Lung Inflammation

Julia Barbara Kral-Pointner ‡^*

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Waltraud Cornelia Schrottmaier ‡^*

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Manuel Salzmann

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Marion Mussbacher

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Georg Johannes Schmidt

²Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

,

Bernhard Moser

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Stefan Heber

³Institute of Physiology, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Birgit Birnecker

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Hannah Paar

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Maria Zellner

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Sylvia Knapp

⁴CEMM, Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria

⁵Department of Medicine I, Laboratory of Infection Biology, Medical University Vienna, Vienna, Austria

,

Alice Assinger

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

,

Gernot Schabbauer

¹Department for Vascular Biology and Thrombosis Research, Centre for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria

› Institutsangaben

Abstract

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.

Keywords

platelets - PI3K - PTEN - acute lung injury - innate leukocyte recruitment

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Referenzen

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