TY - JOUR
T1 - Platelet PI3K Modulates Innate Leukocyte Extravasation during Acid-Induced Acute Lung Inflammation
AU - Kral-Pointner, Julia Barbara
AU - Schrottmaier, Waltraud Cornelia
AU - Salzmann, Manuel
AU - Mussbacher, Marion
AU - Schmidt, Georg Johannes
AU - Moser, Bernhard
AU - Heber, Stefan
AU - Birnecker, Birgit
AU - Paar, Hannah
AU - Zellner, Maria
AU - Knapp, Sylvia
AU - Assinger, Alice
AU - Schabbauer, Gernot
N1 - Publisher Copyright:
© 2019 Georg Thieme Verlag KG Stuttgart - New York.
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - Acute Lung Injury/chemically induced
KW - Animals
KW - Blood Platelets/metabolism
KW - Female
KW - Gene Deletion
KW - Hydrochloric Acid
KW - Hypoxia
KW - Immunity, Innate
KW - Inflammation/chemically induced
KW - Leukocytes/enzymology
KW - Male
KW - Megakaryocytes/cytology
KW - Mice
KW - P-Selectin/metabolism
KW - Peritonitis/metabolism
KW - Phosphatidylinositol 3-Kinases/metabolism
KW - Platelet Function Tests
KW - Pulmonary Edema/chemically induced
KW - Signal Transduction
KW - Tetraspanin 30/metabolism
KW - PTEN
KW - acute lung injury
KW - PI3K
KW - innate leukocyte recruitment
KW - platelets
UR - http://www.scopus.com/inward/record.url?scp=85072746658&partnerID=8YFLogxK
U2 - 10.1055/s-0039-1693693
DO - 10.1055/s-0039-1693693
M3 - Journal article
C2 - 31370072
SN - 0340-6245
VL - 19
SP - 1642
EP - 1654
JO - Thrombosis and Haemostasis
JF - Thrombosis and Haemostasis
IS - 10
ER -