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
AI–Assisted Updates (see footnote below)
A 2018 study on Th17/Treg Imbalance: This research found that an imbalance favoring Th17 cells in the spinal cord contributes to bone cancer pain by promoting microglial activation, linked to increased IL-17 levels.
A 2019 Study on Chemotherapy-Induced Pain: It showed glia-produced IL-17 affects neuron-glial communications and synaptic transmission, contributing to neuropathic pain after chemotherapy.
A 2021 Study on Gut Microbiota: This study revealed gut microbiota influences neuropathic pain by modulating proinflammatory and anti-inflammatory T cells, including Th17 cells, suggesting a dietary link to pain management.
A 2021 Study on Astaxanthin: Astaxanthin was found to reduce neuropathic pain by inhibiting inflammation pathways, potentially affecting IL-17 signaling).
A 2021 Study on Electroacupuncture: Electroacupuncture reduced pain in a rat model by influencing the IL-17-CD4(+) T cell-beta-endorphin axis, highlighting a treatment option.
A 2023 Study on Resolvin D2: Resolvin D2 reduced chronic neuropathic and bone cancer pain by inhibiting IL-17 secretion and astrocyte activation in the spinal cord.
A 2023 Study on Synaptic Plasticity: This study showed IL-17 is involved in neuropathic pain and affects spinal synapse plasticity, suggesting it as a treatment target.
A 2023 Study on Traditional Medicine: Duhuo Jisheng decoction reduced neuroinflammation and pain by suppressing microglial M1 polarization, linked to the IL-17 signaling pathway.
A 2023 Study on Microbiota and Type 17 Immunity: This article discussed how microbiota influences type 17 immunity, which plays a role in tissue repair and pain regulation, an unexpected connection to pain management.
A 2025 Study on Sodium Hydrosulfide: NaHS reduced neuropathic pain by inhibiting IL-17-mediated dopamine neuron death in the brain, offering a novel pain relief mechanism.
Professional AI assistance:
Updates assisted and generated by an Artificial Intelligence (AI) using the professional services of Zlatin Balevsky (contact@balevsky.ai).
Related stories you may like:
Disruption of Brain TNF Homeostasis Elicits Maladaptive Alterations Producing Chronic Pain
The Pathologic Level of Brain TNF is a Therapeutic Target for Chronic Pain Treatment
Microglia: gatekeepers for neuropathic pain
Widespread Pain and Serum IL-8 Levels in Fibromyalgia Patients
TRPV1 Pain Receptor is Expressed and Functionally Active in Human T Lymphocytes
Microglia in Fibromyalgia is Hypersensitive and Overproducing TNF-α