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.