Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain. (1st October 2022)

• Record Type: Journal Article
• Authors: Wu, Wenyao; Zhang, Xianwei; Wang, Shuo; Li, Tian; Hao, Quanshui; Li, Shiyong; Yao, Wenlong; Sun, Rao
• Is Part Of: Neuropharmacology. Volume 217(2022)
• Publication Date: 2022-10-01
• Subjects: cGAS -- STING -- Microglia -- Neuropathic pain; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.109206
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Neuroinflammation plays a vital role in the development of neuropathic pain and is mediated mainly by microglia. Suppressing microglial M1-polarization attenuates neuropathic pain. Recently, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a key mediator of inflammation and shows potential in modulating microglial polarization. In this study, we evaluated whether cGAS-STING is a potential therapeutic target. Spared nerve injury (SNI) surgery was conducted in adult male rats to establish a neuropathic pain model. We showed that SNI promoted microglial M1-polarization and induced cGAS-STING pathway activation in the spinal cord. Double-label immunofluorescence assays showed that cGAS-STING activation mainly occurred in neurons and microglia but not astrocytes. We further conducted in vitro experiments using BV-2 microglial cells. The results showed that LPS-induced microglial M1-polarization was accompanied by cGAS-STING pathway activation, but cGAS-STING inhibition by antagonists suppressed LPS-induced microglial M1-polarization. In vivo, we also showed that a cGAS antagonist and a STING antagonist suppressed the microglial M1-polarization and ameliorated the mechanical allodynia induced by SNI. These findings suggested that the cGAS-STING pathway might be a potential therapeutic target for treating neuropathic pain. However, further research is warranted to verify our findings in female rodents. Highlights: SNI induced activation of cGAS-STING pathway in the spinal cord. Inhibition of cGAS-STING activity attenuated LPS-induced microglial M1-polarization. Inhibition of cGAS-STING activity ameliorated SNI-induced microglial M1-polarization. Inhibition of cGAS-STING activity ameliorated SNI-induced mechanical allodynia.