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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Axons / physiology*
  • CARD Signaling Adaptor Proteins / metabolism
  • Central Nervous System / metabolism
  • Central Nervous System / pathology*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Lectins, C-Type / metabolism*
  • Lipopolysaccharides / pharmacology
  • Mice, Inbred C57BL
  • Microglia / drug effects
  • Microglia / metabolism
  • Myeloid Cells / drug effects
  • Myeloid Cells / metabolism
  • Myeloid Differentiation Factor 88 / metabolism
  • Nerve Regeneration / drug effects*
  • Phagocytosis / drug effects
  • Radiation Tolerance / drug effects
  • Retina / drug effects
  • Retina / metabolism
  • Signal Transduction / drug effects*
  • Toll-Like Receptor 2 / metabolism
  • Zymosan / pharmacology
  • beta-Glucans / adverse effects*


  • CARD Signaling Adaptor Proteins
  • Card9 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Lectins, C-Type
  • Lipopolysaccharides
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptor 2
  • beta-Glucans
  • dectin 1
  • curdlan
  • Zymosan