Platelet p110β mediates platelet-leukocyte interaction and curtails bacterial dissemination in pneumococcal pneumonia

Phosphatidylinositol 3-kinase catalytic subunit p110 beta is involved in tumorigenesis and hemostasis. However, it remains unclear if p110 beta also regulates platelet-mediated immune responses, which could have important consequences for immune modulation during anti-cancer treatment with p110 beta inhibitors. Thus, we investigate how platelet p110 beta affects inflammation and infection. Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110 beta deficiency and pharmacologic inhibition of p110 beta with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination. Platelet p110 beta mediates neutrophil phagocytosis of S. pneumoniae in vitro and curtails bacteremia in vivo. Genetic deficiency or inhibition of platelet p110 beta also impairs macrophage recruitment in an independent model of sterile peritonitis. Our results demonstrate that platelet p110 beta dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection.

Automated summary

Phosphatidylinositol 3-kinase catalytic subunit p110 beta plays a role in tumorigenesis and hemostasis. This study investigates the role of p110 beta in platelet-mediated immune responses and finds that its dysfunction exacerbates infection by impeding leukocyte functions. These findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection.