Activation of innate immune cells stimulates endogenous toll like receptors (TLRs), a family of highly conserved pattern recognition receptors found in invertebrates and vertebrates. TLRs have been implicated in everything from neural plasticity to disease, demonstrating their dichotomous role from neurogenesis to pathogenesis [4]. The most widely studied TLR to date is TLR4 (the receptor for bacterial endotoxin), although 13 TLRs have now been identified [5]. Microglial cells express high levels of TLR4 and respond rapidly to the gram-negative bacterial endotoxin lipopolysaccharide (LPS) to produce inflammatory mediators [6]. Microglial activation of TLR4 is required for astrocyte pro-inflammatory responses [7*]. Neurons have also been shown to express TLR4 [4,8–10] and propagate LPS-induced signaling [11], indicating an unexpected role for neurons in innate immunity and eluding to significant cross-communication among microglia, astrocytes, and neurons that likely characterizes innate immune signaling in the CNS. Brain endothelial cells also express TLR4 and are able to receive neuroimmune stimulation from the brain side and secrete cytokines into the blood or receive stimulation from the blood and secrete cytokines into the brain, suggesting that the blood
