Microglial STING activation alleviates nerve injury-induced neuropathic pain in male but not female mice

• Published in: Brain, behavior, and immunity behavior, and immunity, 2024-03, Vol.117, p.51-65
• Main Authors: Silveira Prudente, Arthur, Hoon Lee, Sang, Roh, Jueun, Luckemeyer, Debora D., Cohen, Cinder F., Pertin, Marie, Park, Chul-Kyu, Suter, Marc R., Decosterd, Isabelle, Zhang, Jun-Ming, Ji, Ru-Rong, Berta, Temugin
• Format: Article
• Language: English
• Subjects: Cytokines; Interferon; Microglia; Neuropathic pain; Sex difference; Spared nerve injury; STING
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2024.01.003

•Microglia contribute to the development and maintenance of neuropathic pain, highlighting a potential target for therapeutic intervention.•STING is predominantly expressed in microglia in the spinal cord and upregulated after nerve injury.•STING activation and IFN-ß alleviate neuropathic pain in male, but not female, mice.•STING activation in female mice leads transcriptional increases of proinflammatory cytokines, which may counteract its analgesic effect.•STING-mediated attenuation of neuropathic pain in male mice requires STING signaling in microglia, but not sensory neurons. Microglia, resident immune cells in the central nervous system, play a role in neuroinflammation and the development of neuropathic pain. We found that the stimulator of interferon genes (STING) is predominantly expressed in spinal microglia and upregulated after peripheral nerve injury. However, mechanical allodynia, as a marker of neuropathic pain following peripheral nerve injury, did not require microglial STING expression. In contrast, STING activation by specific agonists (ADU-S100, 35 nmol) significantly alleviated neuropathic pain in male mice, but not female mice. STING activation in female mice leads to increase in proinflammatory cytokines that may counteract the analgesic effect of ADU-S100. Microglial STING expression and type I interferon-ß (IFN-ß) signaling were required for the analgesic effects of STING agonists in male mice. Mechanistically, downstream activation of TANK-binding kinase 1 (TBK1) and the production of IFN-ß, may partly account for the analgesic effect observed. These findings suggest that STING activation in spinal microglia could be a potential therapeutic intervention for neuropathic pain, particularly in males.