Interleukin-17 Regulates Neuron-Glial Communications, Synaptic Transmission, and Neuropathic Pain after Chemotherapy

Abstract

The proinflammatory cytokine interleukin-17 (IL-17) is implicated in pain regulation. However, the synaptic mechanisms by which IL-17 regulates pain transmission are unknown. Here, we report that glia-produced IL-17 suppresses inhibitory synaptic transmission in the spinal cord pain circuit and drives chemotherapy-induced neuropathic pain. We find that IL-17 not only enhances excitatory postsynaptic currents (EPSCs) but also suppresses inhibitory postsynaptic synaptic currents (IPSCs) and GABAinduced currents in lamina II o somatostatin-expressing neurons in mouse spinal cord slices. IL-17 mainly expresses in spinal cord astrocytes, and its receptor IL-17R is detected in somatostatin-expressing neurons. Selective knockdown of IL-17R in spinal somatostatin-expressing interneurons reduces paclitaxel-induced hypersensitivity. Overexpression of IL-17 in spinal astrocytes is sufficient to induce mechanical allodynia in naive animals. In dorsal root ganglia, IL-17R expression in nociceptive sensory neurons is sufficient and required for inducing neuronal hyperexcitability after paclitaxel. Together, our data show that IL-17/IL-17R mediate neuron-glial interactions and neuronal hyperexcitability in chemotherapy-induced peripheral neuropathy.

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy

“…One study found an increase in P2X7R-dependant glutamate release from cerebrocortical synaptosomes following oxaliplatin treatment; glutamate is the major excitatory CNS neurotransmitter, and its release was eliminated by P2X7R antagonists delivered to the spinal cord (Mannelli et al, 2015). A more positive resting membrane potential and a greater frequency of firing (i.e., hyperactivity) was observed in SOM + excitatory interneurons in the outer lamina of the dorsal horn following paclitaxel treatment; experimentally blocking the IL-17 receptor reduced both hyperactivity and CIPN symptoms (Luo et al, 2019).…”

Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer‐Related Pain by Using Network Pharmacology and Molecular Docking Approach

“…IL-17, secreted by CD4 + T cells, can induce epithelial cells and endothelial cells to synthesize IL-6, PG, and other cytokines, and combination with the TNF signaling pathway to promote inflammation [ 33 ]. Inhibition of IL-17 can effectively relieve pain and inhibit peripheral nerve sensitization [ 34 ]. C-X3-C motif chemokine ligand 1 (CX3CL1) is a kind of chemokine.…”

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…The evidence for this is mainly based on the observed significant antiallodynic and antihyperalgesic effects of GAT-1 inhibitors in rodent models of CIPN. Decreased GABAergic neurotransmission due to excessive IL-17 levels in the spinal cord has been linked to CIPN caused by paclitaxel [171], and the inhibition of GABA reuptake with by NO-711, a selective GABA transporter isoform 1 (GAT-1) inhibitor [172], prevents the development of thermal hyperalgesia and allodynia in paclitaxel-treated mice. NO-711 is also therapeutically effective for pre-existing CIPN [173].…”