For a long time, resident innate immune cells in central and peripheral nervous system, such as macrophages/microglia and mast-cells, have been considered as contributing players in peripheral neurodegeneration. New evidence seems to indicate that this view represented an underestimation of the role of inflammation in the nervous system, attributing to neuroinflammation a critical role of primary driver in peripheral neuropathies and pain. This is the case for autoimmune neuropathies (i.e. Guillain–Barré syndromes), diabetic neuropathy or traumatic nerve injury. Since neuropathic pain, the major feature of the most inflammatory neuropathies, is strongly influenced by the release of proinflammatory cytokines in response to nerve damage from both innate and adaptive immune system, as well as from non-immune cells such as Schwann cells and astrocytes, new therapeutic targets aim to modulate immune response. Moreover, recent studies highlighted new functions for Schwann-cells and astrocytes, who turned out to be not just specialized glial cells, but are also able to act as immune competent cells or immune modulators, drawing a more complex frame in neuropathy onset and development.

Although peripheral neuropathies are heterogeneous disorders (i.e. traumatic, genetic or metabolic origin), a common feature underpins these pathologies: the involvement and interaction between glial and immune cells. Neuroimmune crosstalk in peripheral neuropathies occurs both in peripheral and central nervous system and between them. At peripheral level, during Wallerian degeneration, macrophages, mast cells and Schwann cells orchestrate the first phase of neuropathy, in which myelin aggregates, debris are removed by phagocytosis, lipids are recycled, and a wide spectrum of cytokines, chemokines and trophic factors are released. These processes are necessary for nerve regeneration, recovery of functions and chronicization of pain. At a central level, in the early stages of neuropathy development, the presence of damaged primary afferent sensory neurons in the spinal dorsal or ventral horn induces a marked activity of the microglia, which in turn causes astrocytes reactivity. The pro-inflammatory agents released from these cells favor an inflammatory loop that facilitates the central sensitization and drives neuropathic pain. The complex interactions between neurons and glial cells becomes, then, a potential target for treating the chronic pain state.

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Journal of Pain Management and Therapy
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