Activation of Toll-like receptors (TLR) by pathogens initiates signaling cascades and transcriptional responses that lead to the synthesis and secretion of pro- and anti-inflammatory cytokines as the basis for innate immunity. Inadequate regulation of these cytokines also has damaging sequelae in inflammatory diseases. We find concentrations of cell surface TLR4 and 2 and associated adaptors in dorsal ruffles on the macrophage surface. The GTPase Rab8a is also recruited to the same membrane domains. Rab8a works through multiple effectors and in macrophages we have revealed the immune specific PI3K as a new Rab8a effector in cell signaling. Use of siRNA, pharmacologic inhibitors and bone-marrow derived macrophages from p110у knockout mice were used to show that both Rab8a and PI3K regulate signaling through PI3K/Akt and mTOR to curtail the secretion of proinflammatory cytokines and enhance the secretion of anti-inflammatory cytokines. Rab8a/PI3Kу are key modulators of inflammatory responses in infection and inflammatory disease.