The neuroimmunology of degeneration and regeneration in the peripheral nervous system
Introduction
When an axon in the peripheral nervous system (PNS) is injured, a complex multi-cellular response occurs. The distal axonal segment degenerates, the cell body begins to express regeneration-associated genes (RAGs), and after a delay, the proximal segment forms a growth cone and begins to extend itself toward its denervated target. These processes of axonal degeneration and regeneration require changes not only in the injured neurons but also in non-neuronal cells including Schwann cells and immune cells. In this review, we have summarized recent advances in understanding these changes, focusing in particular on the role of chemokines, cytokines, and immune cells. One picture that will emerge is of macrophages playing two important roles in degeneration and regeneration by creating a pathway in the distal nerve segment conducive to axonal regeneration and by stimulating the axotomized neuronal cell bodies to switch to a regenerative phenotype (Fig. 1).
Section snippets
The biology of Wallerian degeneration (WD)
In 1850, Augustus Waller described changes he observed in axons of cranial nerves after they are disconnected from their cell bodies (Waller, 1850; reprinted in Stoll et al., 2002). The phenomena he described have been collectively termed WD and include among other phenomena the rapid disintegration of the distal axons and the subsequent influx of immune cells that rid the area of debris resulting from this breakdown. This process is thought to be necessary for successful regeneration to occur
The cell body response to axotomy
As noted previously, following axonal injury, peripheral neurons are able to regenerate their axons while central neurons cannot. The ability to regenerate in response to an injury is determined by many factors, including the presence or absence of a permissive environment into which axons can elongate, the influence of non-neuronal cells, and the intrinsic growth capacity of the neuron itself. The latter is dependent on the multitude of changes that occur to the neuronal cell body following
The CL response
The cell body response is thought to underlie the increased regeneration that occurs after a CL. The effect of a CL was first described by McQuarrie and Grafstein (1973) in the context of regeneration in the PNS in their discovery that the growth rate of silver-stained axons in the sciatic nerve increased following a test lesion if that nerve had been lesioned 1–2 wk earlier (Fig. 5b). Their research suggested that a prior CL primes the damaged neuron to initiate its intrinsic growth machinery
Evidence that microglia might promote regeneration after axotomy in the brain and spinal cord
Nissl, who first described chromatolysis, also observed marked glial proliferation in the nucleus of origin following axotomy of cranial motor neurons (Nissl, 1894). Subsequently these cells were shown to be microglia, the CNS’s resident macrophages (Cammermeyer, 1965, Graeber et al., 1988b, Streit et al., 1988). In the facial motor nucleus, for example, microglial proliferation is seen after transection of the facial nerve in the periphery (Blinzinger and Kreutzberg, 1968, Graeber et al., 1988b
Some questions for the future
Current research on nerve regeneration can be divided roughly into two camps depending on the part of the nervous system being studied. Those who focus on the PNS seek to understand the molecular and cellular mechanisms that underlie the degree of regeneration that does occur and how this regeneration might be enhanced. Those who focus on the CNS try to understand what prevents regeneration by most CNS neurons. While these two groups often work in isolation, much benefit could accrue from more
Acknowledgments
Work in the authors’ laboratory is supported by NIDDK 097223 and P30EY11373. J.P.N. and J.A.L. were supported by Training Grant NS 067431. We thank Rebecca Skerrett, Jared Cregg, and Teresa Evans for critical reading of the manuscript and Mike McGraw for help with computer programs.
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These authors contributed equally to this review, and their names are listed alphabetically.