Review The mechanisms of microgliosis and pain following peripheral nerve injury Margarita Calvo ⁎, David L.H. Bennett Wolfson CARD, Kings College London, UK abstract article info Article history: Received 1 July 2011 Revised 10 August 2011 Accepted 18 August 2011 Available online 26 August 2011 Keywords: Microglia Neuropathic pain Peripheral nerve injury Microglia are the resident macrophages in the central nervous system (CNS). Any insult to the CNS homeo- stasis 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 ner- vous 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 en- able 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 in- jury 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 micro- glia 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 in- volve reducing the pro-inflammatory nature of these cells whilst retaining their potential beneficial functions. © 2011 Elsevier Inc. All rights reserved. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Microglial cells respond to neuronal damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Microgliosis in traumatic neuropathic pain models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Models of painful diabetic neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Bone cancer pain models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Models of HIV-induced painful neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Chemotherapy induced painful peripheral neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Microgliosis following peripheral nerve injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Microgliosis is dependent on primary afferent derived injury signals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 Neuregulin-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Metalloproteinase-9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 CCL2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 CCL-21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Fractalkine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 Signals in spinal cord micro-environment regulating microglial responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Activation through pattern of recognition receptors (PRRs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Nucleotides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Interferon γ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 Experimental Neurology 234 (2012) 271–282 ⁎ Corresponding author. E-mail address: margarita.calvo@kcl.ac.uk (M. Calvo). 0014-4886/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2011.08.018 Contents lists available at SciVerse ScienceDirect Experimental Neurology journal homepage: www.elsevier.com/locate/yexnr