title: Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals.
abstract: Toll is a cell surface receptor with well described roles in the developmental patterning of invertebrates and innate immunity in adult Drosophila. Mammalian toll-like receptors represent a family of Toll orthologs that function in innate immunity by recognizing molecular motifs unique to pathogens or injured tissue. One member in this family of pattern recognition receptors, toll-like receptor 3 (TLR3), recognizes viral double-stranded RNA and host mRNA. We examined the expression and function of TLRs in the nervous system and found that TLR3 is expressed in the mouse central and peripheral nervous systems and is concentrated in the growth cones of neurons. Activation of TLR3 by the synthetic ligand polyinosine:polycytidylic acid (poly I:C) or by mRNA rapidly causes growth cone collapse and irreversibly inhibits neurite extension independent of nuclear factor kappaB. Mice lacking functional TLR3 were resistant to the neurodegenerative effects of poly I:C. Neonatal mice injected with poly I:C were found to have fewer axons exiting dorsal root ganglia and displayed related sensorimotor deficits. No effect of poly I:C was observed in mice lacking functional TLR3. Together, these findings provide evidence that an innate immune pattern recognition receptor functions autonomously in neurons to regulate axonal growth and advances a novel hypothesis that this class of receptors may contribute to injury and limited CNS regeneration.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Jill S
authors.initials: JS
authors.lastname: Cameron
authors.forename: Lena
authors.initials: L
authors.lastname: Alexopoulou
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Sloane
authors.forename: Allitia B
authors.initials: AB
authors.lastname: DiBernardo
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Ma
authors.forename: Bela
authors.initials: B
authors.lastname: Kosaras
authors.forename: Richard
authors.initials: R
authors.lastname: Flavell
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Strittmatter
authors.forename: Joseph
authors.initials: J
authors.lastname: Volpe
authors.forename: Richard
authors.initials: R
authors.lastname: Sidman
authors.forename: Timothy
authors.initials: T
authors.lastname: Vartanian
mesh_terms: D000818:Animals; D001369:Axons / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002642:Chick Embryo; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009433:Neural Inhibition / Q000276:immunology*; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000502:physiology*
chemical_list: D006131:Growth Inhibitors; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3