Elsevier

Neuroscience

Volume 302, 27 August 2015, Pages 174-203
Neuroscience

The neuroimmunology of degeneration and regeneration in the peripheral nervous system

https://doi.org/10.1016/j.neuroscience.2014.09.027Get rights and content

Highlights

  • Assessment of the roles for non-neuronal cells and the cytokines they secrete in axonal degeneration and regeneration.

  • After nerve injury, macrophages promote regeneration by acting both in the distal nerve and at axotomized cell bodies.

  • Hematogenous macrophages may not be essential for Wallerian degeneration.

  • The regenerative effects of cytokines at axotomized ganglia require further study.

Abstract

Peripheral nerves regenerate following injury due to the effective activation of the intrinsic growth capacity of the neurons and the formation of a permissive pathway for outgrowth due to Wallerian degeneration (WD). WD and subsequent regeneration are significantly influenced by various immune cells and the cytokines they secrete. Although macrophages have long been known to play a vital role in the degenerative process, recent work has pointed to their importance in influencing the regenerative capacity of peripheral neurons. In this review, we focus on the various immune cells, cytokines, and chemokines that make regeneration possible in the peripheral nervous system, with specific attention placed on the role macrophages play in this process.

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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