Objective

The importance of correct location of immune cell signalling downstream of receptors is a principle factor for defining the qualitative and quantitative nature of immune responses. Lipopolysaccharide initiates TLR4 signaling at the plasma membrane and in the endosomes through TIRAP/MyD88 and TRAM/TRIF adaptors, respectively. It is unclear how the switch between plasma membrane and endosomal TLR4 signaling is coordinated and how it influences the overall innate immune responses to LPS. Herein, we demonstrate that isoform selective phosphoinositol 3-kinases (PI3K) signalling regulate vesicular traffic and signalling downstream of Toll-like receptors. p110δ isoform of PI3K, induces internalization of TLR4 and the dissociation and termination of TIRAP/MyD88 dependent branch of TLR4 signalling pathway. Consequently, inactivation of p110δ prolongs TIRAP-mediated pro-inflammatory signaling, while decreasing TRIF/TRAM-dependent IRF3-mediated IFNβ anti-inflammatory IL-10 production. Mice lacking p110δ catalytic activity is susceptible to endotoxin lethality due to an imbalance between pro- and anti-inflammatory responses. Thus, p110δ PI3K operates as a molecular switch to terminate surface TLR4 signaling through regulation of TLR4 and TIRAP localization.