Neuropathic Pain: New Evidence Linking it to IL-17

Neuropathic Pain
Neuropathic Pain – IL-17

A study published in Molecular Medicine Reports provides further evidence that interleukin (IL)-17 contributes to neuropathic pain through the activation of astrocytes and secretion of proinflammatory cytokines.

Neuropathic pain, defined as pain due to a lesion or disease of the somatosensory system is one of the most severe forms of chronic pain.

Neuropathic pain or chronic pain is a disease syndrome caused by injury to peripheral nerves, the spinal cord or the brain and over 1.5 billion people suffer from this condition. Neuropathic pain and neuropathic pain syndromes include deafferentation pain, diabetic, cancer and ischemic neuropathies, trigeminal neuralgia and nerve injury caused by surgery or trauma.

This also includes central nervous system injury (multiple sclerosis, spinal cord injury) and viral infections (e.g. postherpetic neuralgia).

Astrocytes are the most abundant glial cells in the central nervous system (CNS), and were historically regarded as support cells.  Evidence has demonstrated that astrocytes are important for maintenance of neuropathic pain. In all models of neuropathic pain, such as rhizotomy, chronic constriction injury and spinal nerve ligation, proliferation and activation of astrocytes has been demonstrated, and inhibiting astrocytes in the spinal cord was demonstrated to reduce neuropathic pain. However, the activation of astrocytes and how they mediate neuropathic pain requires further elucidation.

Several pro-inflammatory cytokines contribute to neuropathic pain and hyperalgesia. This includes IL-1β, tumor necrosis factor (TNF), IL-6 and IL-8. Cytokines and chemokines are released by neurons, microglia, astrocytes, macrophages and T cells and activate pain neurons directly and via activation of non-neuronal cells. It appears that enhanced expression of neuronal and glial TNF direct the development and the maintenance of neuropathic pain.

IL-17 is a major player in inflammation and a wide variety of autoimmune disorders.

An increasing body of evidence indicates that IL-17 may also contribute to the development of neuropathic and spinal injury induced pain.

IL-17 or IL-17+ T cells have been observed in patients suffering from arthritic pain, in the sciatic nerve, or in optic nerve injury induced animal models of neuropathic pain. Pain-associated behavior has been demonstrated to be reduced in IL-17 knockout (KO) mice in inflammatory models with complete Freund’s adjuvant (CFA) injection into a plantar or the sciatic nerve and in peripheral nerve injured models.

Intrathecal injection of recombinant IL-17 promotes thermal hyperalgesia of normal mice, which demonstrates that central IL-17 is a key factor in inflammatory pain. The role of IL-17 in the CNS in models of neuropathic pain was suggested by CD4+ T cell infiltration, and its elevated concentration in the spinal cord following nerve injury.

Thus, IL-17A generates hyperexcitability of small to medium-sized dorsal root ganglion (DRG) neurons, implicating regulation of voltage-gated ion channels, and appears to include upregulated sensitivity of TRPV4 ion channels. Interestingly, IL-17 has also been implicated in fibromyalgia.

In the Molecular Medicine Reports study Caixia Sun and colleagues from the Jiangsu University Zhenjiang, China describe an infiltration with CD4+T cells in the spinal cord in a rat model of post-nerve injury. The authors identified CD4/IL‑17 positive cells located at the superficial laminae of the spinal dorsal horn.

The study determined that IL-17 increases in the ipsilateral spinal cord dorsal horn at day 7 post-SNL and observed IL-17 is located in CD4+ cells via double immunostaining.

These observations were associated with an up-regulation of IL‑17, IL‑1β and IL‑6 mRNA expression and high IL-17 protein levels in the spinal cord. Importantly, in vitro, IL‑17 stimulated resting astrocytes to produce IL-1β and IL-6 that may be linked to pain hypersensitivity.

The study suggests that IL-17 is involved in local activation of astrocytes and glial response that via the release of pro-inflammatory cytokine drives and maintains neuropathic pain.

In conclusion, the study demonstrated that IL-17 is involved in maintaining neuropathic pain. Elevated IL-17 may be produced by infiltrated CD4+T cells.

Source: Mol Med Rep 2017 Jan 9;15(1):89-96. Epub 2016 Dec 9.
Read more:  Molecular Medicine Reports