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J. Cell Biol. 175 (2): 209-215

Copyright © 2006 by the Rockefeller University Press.

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Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis

Yinghua Ma1,2,3, Jianxue Li1, Isaac Chiu4, Yawen Wang1,2,3, Jacob A. Sloane1,2,3, Jining Lü5, Bela Kosaras1, Richard L. Sidman1,2, Joseph J. Volpe2,6, , and Timothy Vartanian1,2,3

1 Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02115
2 Program in Neuroscience, 3 Center for Neurodegeneration and Repair, and 4 Center for Blood Research, Graduate Program in Immunology, Harvard Medical School, Boston, MA 02115
5 Pulmonary Center, Boston University School of Medicine, Boston, MA 02118
6 Department of Neurology, Children's Hospital, Boston, MA 02115

Correspondence to Timothy Vartanian: tvartani{at}bidmc.harvard.edu

Abstract: Toll receptors in Drosophila melanogaster function in morphogenesis and host defense. Mammalian orthologues of Toll, the Toll-like receptors (TLRs), have been studied extensively for their essential functions in controlling innate and adaptive immune responses. We report that TLR8 is dynamically expressed during mouse brain development and localizes to neurons and axons. Agonist stimulation of TLR8 in cultured cortical neurons causes inhibition of neurite outgrowth and induces apoptosis in a dissociable manner. Our evidence indicates that such TLR8-mediated neuronal responses do not involve the canonical TLR–NF-{kappa}B signaling pathway. These findings reveal novel functions for TLR8 in the mammalian nervous system that are distinct from the classical role of TLRs in immunity.

Abbreviations used in this paper: CNS, central nervous system; DIG, digoxin; DIV, days in vitro; E, embryonic day; IRAK, interleukin-1 receptor–associated kinase; LPS, lipopolysaccharide; NF-{kappa}B, nuclear factor-{kappa}B; P, postnatal day; PAMPs, pathogen-associated molecular patterns; TLRs, Toll-like receptors.

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