Review
The mechanisms of microgliosis and pain following peripheral nerve injury

https://doi.org/10.1016/j.expneurol.2011.08.018Get rights and content

Abstract

Microglia are the resident macrophages in the central nervous system (CNS). Any insult to the CNS homeostasis will induce a rapid change in microglia morphology, gene expression profile and functional behaviour. These responses of microglia have been collectively known as ‘microgliosis’. Interestingly, damage to the nervous system outside the CNS, such as axotomy of a peripheral nerve, can lead to microgliosis in the spinal cord. There is a variation in the degree of microgliosis depending on the model of nerve injury employed for instance this response is more marked following traumatic nerve injury than in models of chemotherapy induced neuropathy. Following peripheral nerve injury nociceptive inputs from sensory neurons appear to be critical in triggering the development of spinal microgliosis. A number of signalling pathways including growth factors such as Neuregulin-1, matrix metalloproteases such as MMP-9 and multiple chemokines enable direct communication between injured primary afferents and microglia. In addition, we describe a group of mediators which although not demonstrably shown to be released from neurons are known to modulate microglial phenotype. There is a great functional diversity of the microglial response to peripheral nerve injury which includes: Cellular migration, proliferation, cytokine release, phagocytosis, antigen presentation and recruitment of T cells. It should also be noted that in certain contexts microglia may have a role in the resolution of neuro-inflammation. Although there is still no direct evidence demonstrating that spinal microglia have a role in neuropathic pain in humans, these patients present a pro-inflammatory cytokine profile and it is a reasonable hypothesis that these cells may contribute to this inflammatory response. Modulating microglial functions offers a novel therapeutic opportunity following nerve injury which ideally would involve reducing the pro-inflammatory nature of these cells whilst retaining their potential beneficial functions.

Introduction

Microglia are the resident macrophages and the only immune cells in the central nervous system (CNS). Unlike neurons and macroglia, microglia have a mesodermal origin as they are derived from myeloid precursor cells which enter the developing CNS during embryogenesis (Ginhoux et al., 2010, Ransohoff and Perry, 2009). Under the influence of the CNS microenvironment microglia develop fine and long processes and protrusions which are continually surveying their microenvironment (Nimmerjahn et al., 2005). Local cell division at a very low level maintains the number of resident microglia in the brain of rodents (Lawson et al., 1992). When the tightly regulated CNS homeostasis is disturbed by any kind of insult, microglia rapidly change their morphology, gene expression profile and functional behaviour. The local density of microglia increases at the site of injury through migration of these cells from other sites at the CNS and through local proliferation. These responses of microglia have been collectively known as ‘microgliosis’ (reviewed in (Hanisch and Kettenmann, 2007). Interestingly, not only damage to the CNS parenchyma elicits this microglial response; also damage to the nervous system outside the CNS, such as axotomy of a peripheral nerve, can lead to microgliosis both within the dorsal horn of the spinal cord where the injured sensory afferents terminate and within the ventral horn around the cell bodies of injured motor neurons (Eriksson et al., 1993).

Microgliosis following peripheral nerve injury has been shown to contribute to the development of neuropathic pain. Blocking the microglial response with minocycline, a second-generation tetracycline can prevent nerve injury induced hypersensitivity in rats (Ledeboer et al., 2005, Lin et al., 2007, Raghavendra et al., 2003). Furthermore, it has been shown that microglia that have been activated in vitro using ATP can elicit pain related responses in naïve rats when they have been injected intrathecally (Coull et al., 2005, Tsuda et al., 2003).

In this review we will focus on the different aspects of the microglial response to peripheral nerve injury and how this may contribute to the development of neuropathic pain.

Section snippets

Microglial cells respond to neuronal damage

A number of different models of peripheral nerve injury have been developed in order to understand the pathogenesis of neuropathic pain. These involve the administration of a range of injurious stimuli including traumatic, metabolic, toxic and infectious. In all of these models pronounced abnormalities of sensory function are observed which mirror those observed in many neuropathic pain patients. Microgliosis is seen in virtually all models of traumatic nerve injury but may not be universal to

Microgliosis is dependent on primary afferent derived injury signals

Following peripheral nerve injury the accumulation of reactive microglia into the site of injury is orchestrated through different signals which appear in the spinal cord micro-environment and which are released from neurons, astrocytes and other immune cells. Many heterogeneous signals appear to contribute to microgliosis however evidence suggests that these are initially triggered by the injury response of damaged primary afferents. Nociceptive inputs from injured or neighbouring uninjured

Is microgliosis involved in human chronic pain?

Animal models of neuropathic pain have clearly demonstrated that microgliosis is involved in pain pathogenesis. However, we are still lacking direct evidence conclusively demonstrating that spinal microglia also has a role in the pathophysiology of neuropathic pain in humans. A PET scan study in humans using a radio-labelled ligand for the peripheral benzodiazepine receptor suggested the presence of microgliosis in the thalamus of amputees with longstanding phantom limb pain (Banati et al., 2001

Conclusions

There is now a significant body of evidence that microglial cells are active participants in the generation of neuropathic pain. There is a great functional diversity in the microglial response to nerve injury and we are now developing increasing knowledge as to the specific signalling pathways involved in regulating different aspects of microglial function. The detailed study of different models of neuropathic pain would suggest that the importance of these cells in pain generation may differ

Acknowledgments

DLHB and MC would like to acknowledge the financial support of the Wellcome Trust.

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