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

• Published in: Cell reports (Cambridge) Vol. 29; no. 8; pp. 2384 - 2397.e5
• Main Authors: Luo, Hao, Liu, Hui-Zhu, Zhang, Wen-Wen, Matsuda, Megumi, Lv, Ning, Chen, Gang, Xu, Zhen-Zhong, Zhang, Yu-Qiu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.11.2019; Elsevier
• Subjects: allodynia; astrocytes; chemotherapy-induced peripheral neuropathy; Cre-recombinase-dependent adeno-associated virus (AAV); excitatory postsynaptic currents (EPSCs); inhibitory postsynaptic synaptic currents (IPSCs); interleukin-17; neuron-glial interaction; somatostatin-expressing neurons; spinal cord; interleukin-17; somatostatin-expressing neurons; allodynia; excitatory postsynaptic currents (EPSCs); chemotherapy-induced peripheral neuropathy; neuron-glial interaction; astrocytes; spinal cord; inhibitory postsynaptic synaptic currents (IPSCs); Cre-recombinase-dependent adeno-associated virus (AAV)
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.10.085

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 GABA-induced currents in lamina IIo 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. [Display omitted] •IL-17 mediates paclitaxel-induced neuropathic pain by T-cell-independent mechanism•IL-17 regulates pain via neuron-glial interactions both in the spinal cord and DRG•Overexpression of IL-17 in spinal astrocytes induces mechanical allodynia•Blockade of IL-17R suppresses neuronal hyperexcitability induced by paclitaxel Luo et al. find that glia-produced IL-17 regulates synaptic transmission and excitability of spinal SOM+ neurons and DRG small neurons by IL-17R in the DRG and spinal pain circuit. These results suggest that IL-17/IL-17R mediate neuron-glial interactions and drives chemotherapy-induced neuropathic pain.