TLR8 in the Developing Mouse Nervous System

Abstract

In the fruit fly, Toll receptors function during embryogenesis to specify the dorsal-ventral axis in the developing nervous system. In mammals, Toll-like receptors (TLRs) are best known as initiators of the innate immune response through activation of the transcription factor nuclear factor κB (NF-κB). Ma et al . show that TLR8 is dynamically expressed in developing mouse brain and peripheral ganglia. Cultured cortical neurons from embryonic day 16 mice possessed abundant cytosolic TLR8 in the perinuclear region, neurites, and growth cones. Application of a membrane-permeable agonist, resiquinod (R-848), resulted in shorter neurites and an increase in cell death. Cell death, but not the decreased neurite length, was blocked by caspase inhibition. Transduction of a function-blocking antibody against TLR8 partially prevented the R-848-mediated decrease in neurite length and decreased the activation of caspase-3. TLR8 did not activate NF-κB, nor did it promote other hallmarks of activation of the canonical TLR signaling pathway, which suggests that in neurons TLR8 acts through a different pathway. Twenty-four-hour exposures to R-848, which is the time when substantial effects on neurite outgrowth and cell death were noted, caused decreased abundance of IκBα (an inhibitor of the NF-κB pathways as well as an NF-κB-independent transcriptional regulator) and IRAK-4 (interleukin-1 receptor-associated kinase 4). Thus, TLR8 may be a negative regulator of neurite extension and survival during embryogenesis through a noncanonical signaling pathway. Y. Ma, J. Li, I. Chiu, Y. Wang, J. A. Sloane, J. Lü, B. Kosaras, R. L. Sidman, J. J. Volpe, T. Vartanian, Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis. J. Cell Biol. 175 , 209-215 (2006). [Abstract] [Full Text]