Neuronal STING-GAT1 signaling maintains paclitaxel-induced neuropathic pain in the spinal cord.

Abstract

Stimulator of interferon genes (STING), a pivotal immune regulator, has emerged as a contributor to nociception, yet its role in chronic pains remains still unknown. Here, we demonstrate that STING plays a dual role in normal and neuropathic pain in mature male rodents. Stimulator of interferon genes maintains type I interferon (IFN-I) level restraining pain sensitivity in normal and sham control, while activated STING/interferon regulatory factor 3 (IRF3) signaling increases the expression of gamma-aminobutyric acid (GABA) transporter 1 (GAT1) in the spinal cord (SC), thus, generating paclitaxel (PTX)-induced peripheral neuropathy. Genetic interference of STING (STING -/- mice) attenuated PTX-induced mechanical hypersensitivity with attenuated PTX-induced GAT1 increase, preventing PTX-induced increase in tonic GABA A inhibition of the spinal dorsal horn neurons. Stimulator of interferon genes regulates GAT expression through a TANK-binding kinase 1 (TBK1)-IRF3 signaling pathway, with IRF3 as a crucial transcription factor. Silencing neuronal STING, as opposed to its astrocytic counterpart, effectively restrained the PTX-induced mechanical hypersensitivity and GAT1 increase in the SC. Pharmacological inhibition of STING (H-151) efficiently diminished the TBK1/IRF3/GAT1 signaling pathway to alleviate PTX-induced mechanical hypersensitivity. Our findings show that STING-IRF3 serves a dual role: suppressing physiological nociception through IFN-I and acting as a transcriptional regulator of GAT1, contributing to chemotherapy-induced neuropathic pain.