title: Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration.
abstract: Innate immunity can facilitate nervous system regeneration, yet the underlying cellular and molecular mechanisms are not well understood. Here we show that intraocular injection of lipopolysaccharide (LPS), a bacterial cell wall component, or the fungal cell wall extract zymosan both lead to rapid and comparable intravitreal accumulation of blood-derived myeloid cells. However, when combined with retro-orbital optic nerve crush injury, lengthy growth of severed retinal ganglion cell (RGC) axons occurs only in zymosan-injected mice, and not in LPS-injected mice. In mice deficient for the pattern recognition receptor dectin-1 but not Toll-like receptor-2 (TLR2), zymosan-mediated RGC regeneration is greatly reduced. The combined loss of dectin-1 and TLR2 completely blocks the proregenerative effects of zymosan. In the retina, dectin-1 is expressed by microglia and dendritic cells, but not by RGCs. Dectin-1 is also present on blood-derived myeloid cells that accumulate in the vitreous. Intraocular injection of the dectin-1 ligand curdlan [a particulate form of β(1, 3)-glucan] promotes optic nerve regeneration comparable to zymosan in WT mice, but not in dectin-1(-/-) mice. Particulate β(1, 3)-glucan leads to increased Erk1/2 MAP-kinase signaling and cAMP response element-binding protein (CREB) activation in myeloid cells in vivo. Loss of the dectin-1 downstream effector caspase recruitment domain 9 (CARD9) blocks CREB activation and attenuates the axon-regenerative effects of β(1, 3)-glucan. Studies with dectin-1(-/-)/WT reciprocal bone marrow chimeric mice revealed a requirement for dectin-1 in both retina-resident immune cells and bone marrow-derived cells for β(1, 3)-glucan-elicited optic nerve regeneration. Collectively, these studies identify a molecular framework of how innate immunity enables repair of injured central nervous system neurons.
authors: Department of Cell and Developmental Biology, Cellular and Molecular Biology Graduate Program.
authors: Katherine T
authors: KT
authors: Baldwin
authors: Neuroscience Graduate Program, and Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109.
authors: Kevin S
authors: KS
authors: Carbajal
authors: Neuroscience Graduate Program, and Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109 bmsegal@umich.edu rgiger@umich.edu.
authors: Benjamin M
authors: BM
authors: Segal
authors: Department of Cell and Developmental Biology, Cellular and Molecular Biology Graduate Program, Neuroscience Graduate Program, and Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109 bmsegal@umich.edu rgiger@umich.edu.
authors: Roman J
authors: RJ
authors: Giger
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D037181:Lectins, C-Type / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects*; D010587:Phagocytosis / Q000187:drug effects; D011836:Radiation Tolerance / Q000187:drug effects; D012160:Retina / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D015054:Zymosan / Q000494:pharmacology; D047071:beta-Glucans / Q000009:adverse effects*; D000099181:Dectin-1
chemical_list: D053468:CARD Signaling Adaptor Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D015054:Zymosan; D047071:beta-Glucans; D000099181:Dectin-1; C513280:Card9 protein, mouse; C038459:curdlan
keywords: dectin-1; mouse; neuroinflammation; optic nerve; regeneration