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

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.

 

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Platelet p110β, a subunit of phosphatidylinositol 3-kinase, mediates immune responses by promoting platelet-monocyte and neutrophil interactions to prevent bacterial dissemination and exacerbates disease pathogenesis when deficient or inhibited, making it an important target for consideration in anti-cancer treatment with PI3K inhibitors in bacterial infection.

Related Products

Cat.No. Product Name Information
S1169 TGX-221 TGX-221 is a p110β-specific inhibitor with IC50 of 5 nM in a cell-free assay, 1000-fold more selective for p110β than p110α.

Related Targets

PI3K