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Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):2581-6. doi: 10.1073/pnas.1423221112. Epub 2015 Feb 9.

Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration.

Author information

1
Department of Cell and Developmental Biology, Cellular and Molecular Biology Graduate Program.
2
Neuroscience Graduate Program, and Holtom-Garrett Program in Neuroimmunology, Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109.
3
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.
4
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.

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.

KEYWORDS:

dectin-1; mouse; neuroinflammation; optic nerve; regeneration

PMID:
25675510
PMCID:
PMC4345569
DOI:
10.1073/pnas.1423221112
[Indexed for MEDLINE]
Free PMC Article

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