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  2. Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain

Pharmacological inhibition of the cGAS-STING signaling pathway suppresses microglial M1-polarization in the spinal cord and attenuates neuropathic pain

  • Neuropharmacology. 2022 Oct 1;217:109206. doi: 10.1016/j.neuropharm.2022.109206.
Wenyao Wu 1 Xianwei Zhang 1 Shuo Wang 1 Tian Li 2 Quanshui Hao 3 Shiyong Li 1 Wenlong Yao 1 Rao Sun 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 2 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Anesthesiology, Huanggang Central Hospital of Yangtze University, Huanggang, China.
  • 4 Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: raosun@hust.edu.cn.
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.

Keywords

Microglia; Neuropathic pain; STING; cGAS.

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