Immune-Mediated Repair and Regeneration of the Nervous System

Abstract

All animals have the ability to repair damaged or diseased tissues. The degree to which regeneration can occur can vary from some invertebrates and vertebrates regenerating entire limbs, to mammals which have a very restricted regenerative capacity. While damages to muscle, peripheral nerves, and, to a limited extent, liver initiates regenerative programs to restore function, the central nervous system (CNS) healing is largely incomplete. Rapid and efficient clearance of cellular debris is necessary for tissue regeneration to occur. Myelin debris can be found in the white matter tracts years after an injury to the CNS in both humans and primates. Myelin is a membrane outgrowth of glial cells that ensheath axons purpose of which is to allow fast saltatory conduction of action potential along the axon. Myelin sheath also has within it many proteins that are inhibitory for axon growth, presumably to prevent errant axon sprouting. The prolonged presence of myelin-associated inhibitors of axon regeneration is thought to be a major contributor to the failure of recovery after injury to the CNS. Myelin in the peripheral nervous system (PNS) also contains inhibitors of axon regeneration. In stark contrast to the CNS, injury to the PNS results in rapid clearance of myelin thereby making the environment permissive for axon regeneration. It has been demonstrated that endogenous antibodies are required for rapid and robust clearance of myelin debris after injury to the PNS. Endogenous antibodies enter the site of injury and bind myelin debris which recruits macrophages to rapidly phagocytose the debris. It was hypothesized that Th2 activated (alternatively activated) macrophages (or M2 macrophages) are playing a critical role in the clearance of myelin and other apoptotic debris in PNS injury. Perhaps, then, this might be another explanation why the PNS recovers and the CNS fails to recover after injury. This would have significant implications for people who suffer from spinal cord injuries.