Molecular Mechanisms of Immune-Mediated Axon Regeneration in the Injured Central Nervous System.

Abstract

In the injured adult mammalian central nervous system (CNS), severed axons fail to undergo spontaneous regeneration, leading to permanent neurological deficits, such as paralysis following spinal cord injury, and cognitive impairment following traumatic brain injury or stroke. A large body of work has established that neuron intrinsic and extrinsic mechanisms pose barriers to efficient CNS repair. Inhibitory molecules, including myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs), are expressed by injured CNS tissue and complex with neuronal surface receptors to prevent regenerative growth of axons. Following retro-orbital crush injury to the mouse optic nerve, injured retinal ganglion cell (RGC) axons do not normally grow beyond the injury site. Deletion of multiple CSPG receptors enables significant, though modest, regeneration of RGC axons. In these mice, RGC axon regeneration can be greatly enhanced by induction of a local immune response. The underlying mechanisms of immune-mediated neurorepair are poorly understood. Here I show that post-injury manipulation of specific immunomodulatory pathways promotes extensive growth of injured RGC axons. Intraocular injection of zymosan, a yeast cell wall extract, leads to a rapid accumulation of blood-derived immune cells in the vitreous, and enables robust RGC axon regeneration by engaging the pattern recognition receptors dectin-1 and Toll-like receptor-2 (TLR2). Dectin-1 is expressed by retina-resident 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 beta-glucan) elicits robust regeneration in WT, but not in dectin-1−/− mice. Studies with dectin-1−/−/WT reciprocal bone marrow chimeric mice revealed a requirement for dectin-1 on both retina-resident immune cells and bone-marrow derived cells for beta-glucan-elicited optic nerve regeneration. Collectively, these studies identify a molecular framework for how innate immunity enables repair of injured central nervous system neurons.