Platelet p110β mediates platelet-leukocyte interaction and curtails bacterial dissemination in pneumococcal pneumonia
Waltraud C. Schrottmaier, Julia B. Kral‐Pointner, Manuel Salzmann, Marion Mußbacher, Anna Schmuckenschlager, Anita Pirabe, Laura Brunnthaler, Mario Kuttke, Bárbara Maier, Stefan Heber, Hannes Datler, Yasemin Ekici, Birgit Niederreiter, Ulrike Heber, Bo Blomgren, Anna-Dorothea Gorki, Cecilia Söderberg‐Nauclér, Bernard Payrastre, Marie‐Pierre Gratacap, Sylvia Knapp, Gernot Schabbauer, Alice Assinger
Abstract
Phosphatidylinositol 3-kinase catalytic subunit p110β is involved in tumorigenesis and hemostasis. However, it remains unclear if p110β also regulates platelet-mediated immune responses, which could have important consequences for immune modulation during anti-cancer treatment with p110β inhibitors. Thus, we investigate how platelet p110β affects inflammation and infection. Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110β deficiency and pharmacologic inhibition of p110β with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination. Platelet p110β mediates neutrophil phagocytosis of S. pneumoniae in vitro and curtails bacteremia in vivo. Genetic deficiency or inhibition of platelet p110β also impairs macrophage recruitment in an independent model of sterile peritonitis. Our results demonstrate that platelet p110β dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection.