IL-17A/IL-17RA signaling drives microglial mtDNA-cGAS/STING axis to promote synaptic and cognitive impairment in chronic migraine

Cognitive dysfunction is increasingly recognized as a major contributor to disability in chronic migraine (CM), yet the mechanisms linking neuroinflammation to synaptic dysfunction and cognitive decline remain poorly understood. Interleukin-17A (IL-17A) has emerged as an important regulator of neuroimmune interactions in neurological disorders; however, its role in migraine-associated cognitive impairment remains unknown. A nitroglycerin (NTG)-induced mouse model of CM was combined with behavioral testing, transcriptomic profiling, immunohistochemistry, molecular analyses, and in vitro microglial studies. IL-17A neutralization, Il17ra knockdown, antioxidant treatment, and pharmacological inhibition of STING were used to dissect the underlying mechanisms. Repeated NTG administration induced mechanical hypersensitivity, cognitive impairment, and elevated cortical IL-17A expression. Neutralization of IL-17A significantly alleviated both nociceptive sensitization and cognitive deficits. Transcriptomic analyses revealed activation of IL-17 and cytosolic DNA-sensing pathways, accompanied by suppression of synaptic-related programs. Mechanistically, IL-17RA was predominantly upregulated in cortical microglia, where IL-17A promoted oxidative stress, mitochondrial dysfunction, and mitochondrial DNA (mtDNA) release. Cytosolic mtDNA subsequently activated the cGAS/STING pathway, driving inflammatory microglial remodeling and excessive synaptic engulfment. Pharmacological or genetic interruption of this signaling cascade attenuated cGAS/STING activation, reduced microglial inflammatory responses, and preserved synaptic integrity. Importantly, STING inhibition markedly suppressed microglial synaptic engulfment and rescued synaptic deficits in repeated NTG-treated mice. Our findings identify an IL-17A/IL-17RA-ROS-mtDNA-cGAS/STING signaling cascade in microglia that links neuroinflammation to synaptic pathology chronic migraine-like conditions. By driving inflammatory microglial remodeling and excessive synaptic pruning, this pathway contributes to migraine-associated cognitive dysfunction and represents a potential therapeutic target for preventing migraine chronification and its cognitive impairments. Not applicable.