Chemotherapy-induced peripheral neuropathy (CIPN) and associated neuropathic pain is a debilitating adverse effect of cancer treatment. Current understanding of the mechanisms underpinning CIPN is limited and there are no effective treatment strategies. In this study, we treated male C57BL/6J mice with 4 cycles of either Paclitaxel (PTX) or Oxaliplatin (OXA) over a week and tested pain hypersensitivity and changes in peripheral immune responses and neuroinflammation on days 7 and 13 post 1st injection. We found that both PTX and OXA caused significant mechanical allodynia. In the periphery, PTX and OXA significantly increased circulating CD4+ and CD8+ T-cell populations. OXA caused a significant increase in the percentage of interleukin-4+ lymphocytes in the spleen and significant down-regulation of regulatory T (T-reg) cells in the inguinal lymph nodes. However, conditional depletion of T-reg cells in OXA-treated transgenic DEREG mice had no additional effect on pain sensitivity. Furthermore, there was no leukocyte infiltration into the nervous system of OXA- or PTX-treated mice. In the peripheral nervous system, PTX induced expression of the neuronal injury marker activating transcription factor-3 in IB4+ and NF200+ sensory neurons as well as an increase in the chemokines CCL2 and CCL3 in the lumbar dorsal root ganglion. In the central nervous system, PTX induced significant astrocyte activation in the spinal cord dorsal horn, and both PTX and OXA caused reduction of P2ry12+ homeostatic microglia, with no measurable changes in IBA-1+ microglia/macrophages in the dorsal and ventral horns. We also found that PTX induced up-regulation of several inflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL11, CCL4, CCL3, IL-12p70 and GM-CSF) in the spinal cord. Overall, these findings suggest that PTX and OXA cause distinct pathological changes in the periphery and nervous system, which may contribute to chemotherapy-induced neuropathic pain.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterised by widespread areas of focal demyelination. Its aetiology and pathogenesis remain unclear despite substantial insights gained through studies of animal models, most notably experimental autoimmune encephalomyelitis (EAE). MS is widely believed to be immune-mediated and pathologically attributable to myelin-specific autoreactive CD4+ T cells. In recent years, MS research has expanded beyond its focus on CD4+ T cells to recognise the contributions of multiple immune and glial cell types to the development, progression, and amelioration of the disease. This review summarises evidence of T and B lymphocyte, natural killer cell, macrophage/microglial, astrocytic, and oligodendroglial involvement in both EAE and MS and the intercommunication and influence of each cell subset in the inflammatory process. Despite important advances in the understanding of the involvement of these cell types in MS, many questions still remain regarding the various subsets within each cell population and their exact contribution to different stages of the disease.

No abstract

Pain is a widespread and debilitating symptom of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. Although central neuroinflammation and demyelination have been implicated in MS-related pain, the contribution of peripheral and central mechanisms during different phases of the disease remains unclear. In this study, we used the animal model experimental autoimmune encephalomyelitis (EAE) to examine both stimulus-evoked and spontaneous pain behaviors, and neuroinflammatory changes, over the course of chronic disease. We found that mechanical allodynia of the hind paw preceded the onset of clinical EAE but was unmeasurable at clinical peak. This mechanical hypersensitivity coincided with increased microglial activation confined to the dorsal horn of the spinal cord. The development of facial mechanical allodynia also emerged in preclinical EAE, persisted at the clinical peak, and corresponded with pathology of the peripheral trigeminal afferent pathway. This included T cell infiltration, which arose prior to overt central lesion formation and specific damage to myelinated neurons during the clinical peak. Measurement of spontaneous pain using the mouse grimace scale, a facial expression-based coding system, showed increased facial grimacing in mice with EAE during clinical disease. This was associated with multiple peripheral and central neuroinflammatory changes including a decrease in myelinating oligodendrocytes, increased T cell infiltration, and macrophage/microglia and astrocyte activation. Overall, these findings suggest that different pathological mechanisms may underlie stimulus-evoked and spontaneous pain in EAE, and that these behaviors predominate in unique stages of the disease.

Sensory problems such as neuropathic pain are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the CNS. Regulatory T (Treg) cells are critical for maintaining immune homeostasis, but their role in MS-associated pain remains unknown. Here, we demonstrate that Treg cell ablation is sufficient to trigger experimental autoimmune encephalomyelitis (EAE) and facial allodynia in immunized female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin-35 (IL-35) significantly reduced facial stimulus-evoked pain and spontaneous pain independent of disease severity and increased myelination of the facial nociceptive pathway. The effects of intrathecal IL-35 therapy were Treg-cell dependent and associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes and reduced monocyte infiltration in the trigeminal afferent pathway. We present evidence for a beneficial role of Treg cells and IL-35 in attenuating pain associated with EAE independently of motor symptoms by decreasing neuroinflammation and increasing myelination.

Regulatory T (Treg) cells are a special subpopulation of immunosuppressive T cells that are essential for sustaining immune homeostasis. They maintain self-tolerance, inhibit autoimmunity, and act as critical negative regulators of inflammation in various pathological states including autoimmunity, injury, and degeneration of the nervous system. Treg cells are known to convey both beneficial and detrimental influences in certain disease contexts, and accumulating research suggests that their action may be altered in a range of peripheral and central nervous system pathologies. In this review, we discuss emerging evidence for the dichotomous role of Treg cells in various neurological pathologies including multiple sclerosis, Guillain-Barré syndrome, neuropathic pain, traumatic central nervous system injury, stroke, and neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. We are in the early stages of uncovering the role of Treg cells in these conditions, and a better understanding of the ways in which these cells operate in the nervous system will enable us to develop novel therapeutic interventions.

No abstract

No abstract