Fig. 1

Neuro(auto)immune response to sciatic nerve injury. Using the sciatic nerve as an example, this figure provides a snapshot overview of the events that may underlie a neuroimmune response, which may involve aspects of aberrant autoimmune interactions, to a peripheral nerve injury. Following nerve injury, depolarizing voltages as well as positive and negative injury signaling mechanisms transduce information about the injury to the DRG, allowing for the coordination of a regenerative response. From the DRG, signals are transmitted from the periphery to the spinal cord by cytokines, nucleotides, and chemokines, resulting in microglial and astrocytic activation in the dorsal spinal horn. Ultimately, these signals are transduced to centers in the brain for further processing. Various immune populations are recruited to the site of sciatic nerve injury and the ipsilateral DRG. The factors influencing immune cell recruitment are complex and include toll-like receptors, Schwann cells, and other immune populations, cytokines, and chemokines. The activity of these immune cells is dynamic, and in many instances, may not be localized to a singular region. In the context of sciatic nerve injury, there is evidence of neutrophil, dendritic cell, macrophage, and T lymphocyte presence at the site of injury and ipsilateral DRG. The latter two immune cell types produce pro-inflammatory cytokines such as TNF-α, which can activate nociceptive nerve terminals. Th1 lymphocytes produce IFN-γ, which regulates macrophage activity and is detected at the sciatic nerve after injury. IL-17, produced by Th17 lymphocytes, plays a role in mediating infiltration of T lymphocytes to the site of injury as well as activation of microglia and astrocytes. B lymphocytes are also recruited to the site of injury and can produce pathological IgG autoantibodies, including those that form an immune complex when bound to gangliosides on neuronal and axonal cell surfaces. Autoantibody production may be promoted by IL-10, which is produced by Th2 lymphocytes and is detected at the sciatic nerve after injury. Anti-ganglioside autoantibody immune complexes interact with FcγRIII on macrophages and glial cells at the site of injury, leading to pro-inflammatory cytokine production and inhibition of axon regeneration, thus likely resulting in chronic pain. These immune complexes may interact with FcγRI in the DRG; this interaction generates excitable activity in nociceptive neurons and may result in the secretion of CGRP and substance P in the DRG. Both CGRP and substance P are involved in signal transduction and the latter neuropeptide may promote long-term potentiation of excitable currents generated via the NMDAR. Prolonged hyper-excitability of nociceptive neurons may eventually result in chronic pain