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

Abstract

Summary: 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. : 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. Keywords: interleukin-17, chemotherapy-induced peripheral neuropathy, excitatory postsynaptic currents (EPSCs), inhibitory postsynaptic synaptic currents (IPSCs), somatostatin-expressing neurons, Cre-recombinase-dependent adeno-associated virus (AAV), astrocytes, allodynia, spinal cord, neuron-glial interaction