Nociceptors and immune cells both protect the host from potential threats to homeostasis. There is growing evidence for bidirectional signalling between these two systems, and the underlying mechanisms are beginning to be elucidated. An understanding is emerging of how both the adaptive and innate immune systems can activate and sensitize nociceptors, and, reciprocally, how nociceptors modulate immune cells. In this Review, we discuss how these interactions can be adaptive and useful to the organism but also consider when such signalling might be maladaptive and pathophysiological, contributing to immune-mediated diseases and persistent pain states.
Neuregulin 1 acts as an axonal signal that regulates multiple aspects of Schwann cell development including the survival and migration of Schwann cell precursors, the ensheathment of axons and subsequent elaboration of the myelin sheath. To examine the role of this factor in remyelination and repair following nerve injury, we ablated neuregulin 1 in the adult nervous system using a tamoxifen inducible Cre recombinase transgenic mouse system. The loss of neuregulin 1 impaired remyelination after nerve crush, but did not affect Schwann cell proliferation associated with Wallerian degeneration or axon regeneration or the clearance of myelin debris by macrophages. Myelination changes were most marked at 10 days after injury but still apparent at 2 months post-crush. Transcriptional analysis demonstrated reduced expression of myelin-related genes during nerve repair in animals lacking neuregulin 1. We also studied repair over a prolonged time course in a more severe injury model, sciatic nerve transection and reanastamosis. In the neuregulin 1 mutant mice, remyelination was again impaired 2 months after nerve transection and reanastamosis. However, by 3 months post-injury axons lacking neuregulin 1 were effectively remyelinated and virtually indistinguishable from control. Neuregulin 1 signalling is therefore an important factor in nerve repair regulating the rate of remyelination and functional recovery at early phases following injury. In contrast to development, however, the determination of myelination fate following nerve injury is not dependent on axonal neuregulin 1 expression. In the early phase following injury, axonal neuregulin 1 therefore promotes nerve repair, but at late stages other signalling pathways appear to compensate.
Greater emphasis on the study of intact cellular networks in their physiological environment has led to rapid advances in intravital imaging of the central nervous system (CNS), while the peripheral system remains largely unexplored. To assess large networks of sensory neurons, we selectively label primary afferents with GCaMP6s in male and female C57bl/6 mice and visualize their functional responses to peripheral stimulation in vivo. We show that we are able to monitor the activity of hundreds of sensory neurons simultaneously, with sufficient sensitivity to detect, in most cases, single action potentials with a typical rise time of around 200 ms, and an exponential decay with a time constant of approximately 700 ms. With this technique we are able to characterize the responses of large populations of sensory neurons to innocuous and noxious mechanical and thermal stimuli under normal and inflammatory conditions. We demonstrate that the majority of primary afferents are polymodal with between 50–80% of thermally sensitive DRG neurons responding also to noxious mechanical stimulation. We also specifically assess the small population of peripheral cold neurons and demonstrate significant sensitization to cooling after a model of sterile and persistent inflammation, with significantly increased sensitivity already at decreases of 5°C when compared to uninflamed responses. This not only reveals interesting new insights into the (patho)physiology of the peripheral nervous system but also demonstrates the sensitivity of this imaging technique to physiological changes in primary afferents.
G-protein receptor 84 (GPR84) is an orphan receptor that is induced markedly in monocytes/macrophages and microglia during inflammation, but its pathophysiological function is unknown. Here, we investigate the role of GPR84 in a murine model of traumatic nerve injury. Naive GPR84 knock-out (KO) mice exhibited normal behavioral responses to acute noxious stimuli, but subsequent to partial sciatic nerve ligation (PNL), KOs did not develop mechanical or thermal hypersensitivity, in contrast to wild-type (WT) littermates. Nerve injury increased ionized calcium binding adapter molecule 1 (Iba1) and phosphorylated p38 MAPK immunoreactivity in the dorsal horn and Iba1 and cluster of differentiation 45 expression in the sciatic nerve, with no difference between genotypes. PCR array analysis revealed that Gpr84 expression was upregulated in the spinal cord and sciatic nerve of WT mice. In addition, the expression of arginase-1, a marker for anti-inflammatory macrophages, was upregulated in KO sciatic nerve. Based on this evidence, we investigated whether peripheral macrophages behave differently in the absence of GPR84. We found that lipopolysaccharide-stimulated KO macrophages exhibited attenuated expression of several proinflammatory mediators, including IL-1, IL-6, and TNF-␣. Forskolin-stimulated KO macrophages also showed greater cAMP induction, a second messenger associated with immunosuppression. In summary, our results demonstrate that GPR84 is a proinflammatory receptor that contributes to nociceptive signaling via the modulation of macrophages, whereas in its absence the response of these cells to an inflammatory insult is impaired.
Down Syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and results in a spectrum of phenotypes including learning and memory deficits, and motor dysfunction. It has been hypothesized that an additional copy of a few Hsa21 dosage-sensitive genes causes these phenotypes, but this has been challenged by observations that aneuploidy can cause phenotypes by the mass action of large numbers of genes, with undetectable contributions from individual sequences. The motor abnormalities in DS are relatively understudied—the identity of causative dosage-sensitive genes and the mechanism underpinning the phenotypes are unknown. Using a panel of mouse strains with duplications of regions of mouse chromosomes orthologous to Hsa21 we show that increased dosage of small numbers of genes causes locomotor dysfunction and, moreover, that the Dyrk1a gene is required in three copies to cause the phenotype. Furthermore, we show for the first time a new DS phenotype: loss of motor neurons both in mouse models and, importantly, in humans with DS, that may contribute to locomotor dysfunction.
Greater emphasis on the study of intact cellular networks in their physiological environment has led to rapid advances in intravital imaging in the central nervous system, while the peripheral system remains largely unexplored. To assess large networks of sensory neurons we selectively label primary afferents with GCaMP6s and visualise their functional responses in vivo to peripheral stimulation. We show that we are able to monitor simultaneously the activity of hundreds of sensory neurons with sensitivity sufficient to detect, in most cases, single action potentials with a typical rise time of around 200 milliseconds, and an exponential decay with a time constant of approximately 700 milliseconds. Using this sensitive technique we are able to show that large scale recordings demonstrate the recently disputed polymodality of nociceptive primary afferents with between 40-80% of thermally sensitive DRG neurons responding also to noxious mechanical stimulation. We also specifically assess the small population of peripheral cold fibres and demonstrate significant sensitisation to cooling after a model of sterile and persistent inflammation, with significantly increased sensitivity already at decreases of 5°C when compared to uninflamed responses. This not only reveals interesting new insights into the (patho)physiology of the peripheral nervous system but also demonstrates the sensitivity of this imaging technique to physiological changes in primary afferents.Significance StatementMost of our functional understanding of the peripheral nervous system has come from single unit recordings. However, the acquisition of such data is labour-intensive and usually ‘low yield’. Moreover, some questions are best addressed by studying populations of neurons. To this end we report on a system that monitors activity in hundreds of single sensory neurons simultaneously, with sufficient sensitivity to detect in most cases single action potentials. We use this technique to characterise nociceptor properties and demonstrate polymodality in the majority of neurons and their sensitization under inflammatory conditions. We therefore believe this approach will be very useful for the studies of the somatosensory system in general and pain in particular.
Correct communication between immune cells and peripheral neurons is crucial for the protection of our bodies. Its breakdown is observed in many common, often painful conditions, including arthritis, neuropathies, and inflammatory bowel or bladder disease. Here, we have characterised the immune response in a mouse model of neuropathic pain using flow cytometry and cell-type-specific RNA sequencing (RNA-seq). We found few striking sex differences, but a very persistent inflammatory response, with increased numbers of monocytes and macrophages up to 3 1/2 months after the initial injury. This raises the question of whether the commonly used categorisation of pain into “inflammatory” and “neuropathic” is one that is mechanistically appropriate. Finally, we collated our data with other published RNA-seq data sets on neurons, macrophages, and Schwann cells in naive and nerve injury states. The result is a practical web-based tool for the transcriptional data mining of peripheral neuroimmune interactions. http://rna-seq-browser.herokuapp.com/
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