The p110δ isoform of PI3K modulates TLR4 signalling and is crucial for survival from endotoxin and Escherichia coli infection (P4023)

Abstract

Abstract Sepsis, a systemic immune response to severe bacterial infection, is a leading cause of death in critical care medicine caused by dysregulated immune response to bacteria endotoxin LPS which is recognised by TLR4. The p110δ isoform of PI3K is expressed mostly on leukocytes and has been shown to be important in leukocyte recruitment to sites of inflammation and infection. We report that pharmacological or genetic inhibition of p110δ signalling led to increased expression of TLR4 upon LPS stimulation an effect which was not observed for p110α and p110β. Differential cell counting showed higher numbers of inflammatory cells in the peritoneum of p110δ knock-in [p110δ(D910A)] mice compared to wild type mice. Macrophages from p110δ(D910A) mice induced higher proinflammatory cytokines compared to WT mice in response to LPS. In addition, absence of p110δ activity led to mortality in an otherwise non lethal dose of LPS accompanied by exaggerated production of proinflammatory cytokines. We authenticate our findings by showing that p110δ(D910A) mice are unable to recover from a non lethal dose of Escherichia coli infection. Thus modulation of p110δ signalling is a potential therapeutic target in acute inflammation and sepsis