Neurogenesis — the formation of new neurons in the adult brain — is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes1. The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila2 and innate immune activity in mammals3,4, regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKCα/β-dependent activation of the NF-κB signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.
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Emsley, J. G., Mitchell, B. D., Kempermann, G. & Macklis, J. D. Adult neurogenesis and repair of the adult CNS with neural progenitors, precursors, and stem cells. Prog. Neurobiol. 75, 321–341 (2005).
Anderson, K. V., Jurgens, G. & Nusslein-Volhard, C. Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell 42, 779–789 (1985).
Akira, S. & Takeda, K. Toll-like receptor signalling. Nature Rev. Immunol. 4, 499–511 (2004).
Janeway, C. A., Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).
Kielian, T. Toll-like receptors in central nervous system glial inflammation and homeostasis. J. Neurosci. Res. 83, 711–730 (2006).
Rivest, S. Molecular insights on the cerebral innate immune system. Brain Behav. Immun. 17, 13–19 (2003).
Bsibsi, M., Ravid, R., Gveric, D. & van Noort, J. M. Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol. 61, 1013–1021 (2002).
Olson, J. K. & Miller, S. D. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J. Immunol. 173, 3916–3924 (2004).
Nguyen, M. D., Julien, J. P. & Rivest, S. Innate immunity: the missing link in neuroprotection and neurodegeneration? Nature Rev. Neurosci. 3, 216–227 (2002).
Hayes, N. L. & Nowakowski, R. S. Dynamics of cell proliferation in the adult dentate gyrus of two inbred strains of mice. Brain Res. Dev. Brain Res. 134, 77–85 (2002).
Cameron, H. A. & McKay, R. D. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J. Comp. Neurol. 435, 406–417 (2001).
Song, H., Stevens, C. F. & Gage, F. H. Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39–44 (2002).
Palmer, T. D., Willhoite, A. R. & Gage, F. H. Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479–494 (2000).
McGettrick, A. F. & O'Neill, L. A. The expanding family of MyD88-like adaptors in Toll-like receptor signal transduction. Mol. Immunol. 41, 577–582 (2004).
Uematsu, S. & Akira, S. Toll-like receptors and innate immunity. J. Mol. Med. 84, 712–725 (2006).
Zhang, G. & Ghosh, S. Toll-like receptor-mediated NF-κB activation: a phylogenetically conserved paradigm in innate immunity. J. Clin. Invest. 107, 13–19 (2001).
Asehnoune, K., Strassheim, D., Mitra, S., Yeol Kim, J. & Abraham, E. Involvement of PKCα/β in TLR4 and TLR2 dependent activation of NF-κB. Cell Signal 17, 385–394 (2005).
Spitzer, J. H., Visintin, A., Mazzoni, A., Kennedy, M. N. & Segal, D. M. Toll-like receptor 1 inhibits Toll-like receptor 4 signaling in endothelial cells. Eur. J. Immunol. 32, 1182–1187 (2002).
Ziv, Y. et al. Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neurosci. 9, 268–275 (2006).
Monje, M. L., Toda, H. & Palmer, T. D. Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765 (2003).
Ekdahl, C. T., Claasen, J. H., Bonde, S., Kokaia, Z. & Lindvall, O. Inflammation is detrimental for neurogenesis in adult brain. Proc. Natl Acad. Sci. USA 100, 13632–13637 (2003).
Iosif, R. E. et al. Tumor necrosis factor receptor 1 is a negative regulator of progenitor proliferation in adult hippocampal neurogenesis. J. Neurosci. 26, 9703–9712 (2006).
Johnson, G. B., Brunn, G. J. & Platt, J. L. Activation of mammalian Toll-like receptors by endogenous agonists. Crit. Rev. Immunol. 23, 15–44 (2003).
Pluchino, S. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003).
Butovsky, O. et al. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149–160 (2006).
We thank Prof. Akira, Dr Uematsu and Prof. Irun Cohen for the TLR-deficient mice, and Dr Stefan Jung for the CX3CR1GFP mice. We thank Shelley Schwarzbaum and Shirley R. Smith for editing, and Shifra Ben-Dor for bioinformatical assistance. M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. This study was supported, in part, by an NRSAD award and by a research grant from Mr and Mrs Richard D. Siegal.
The authors declare no competing financial interests.
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Rolls, A., Shechter, R., London, A. et al. Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9, 1081–1088 (2007). https://doi.org/10.1038/ncb1629
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