Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning

Sepsis is a severe global health issue with high mortality rates, and sepsis-associated encephalopathy (SAE) further exacerbates this risk. While recent studies have shown the migration of gut immune cells to the lungs after sepsis, their impact on the central nervous system remains unclear. Our research demonstrates that sepsis could induce the migration of IL-7Rhigh CD8low γδ T17 cells from the small intestine to the meninges, where they secrete IL-17A, impairing mitochondrial function in microglia and activating the cGAS-STING-C1q pathway. This process is accompanied by inhibited ubiquitination of STING at the K150 site, resulting in STING accumulation and increased release of C1q-tagged hippocampal synapses, which are subsequently pruned by activated microglia. Importantly, 4-Octyl itaconate mitigates the excessive synaptic pruning by inhibiting γδ T17 cell migration and promoting STING ubiquitination, thereby alleviating SAE. Our findings reveal a novel mechanism of synaptic pruning by microglia via the cGAS-STING-C1q pathway, emphasize the critical role of gut-derived γδ T17 cell migration to the meninges in SAE, and highlight the importance of STING ubiquitination in modulating C1q-mediated excessive synaptic pruning.

脓毒症（Sepsis）是全球范围内严重的健康问题，死亡率居高不下，而脓毒症相关性脑病（sepsis-associated encephalopathy, SAE）进一步加剧了这一风险。尽管近期研究表明脓毒症后肠道免疫细胞会迁移至肺部，但其对中枢神经系统（central nervous system）的影响仍不明确。本研究表明，脓毒症可诱导IL-7R高表达CD8低表达的γδ T17细胞（γδ T17 cells）从回肠迁移至脑膜（meninges），这些细胞在脑膜处分泌白细胞介素17A（IL-17A），损害小胶质细胞（microglia）的线粒体功能（mitochondrial function）并激活cGAS-STING-C1q通路（cGAS-STING-C1q pathway）。该过程伴随着STING在K150位点（K150 site）的泛素化（ubiquitination）受抑制，导致STING积累以及C1q标记的海马突触（hippocampal synapses）释放增加，这些突触随后被活化的小胶质细胞修剪。重要的是，4-辛基衣康酸酯（4-Octyl itaconate）通过抑制γδ T17细胞迁移和促进STING泛素化，减轻了过度的突触修剪（synaptic pruning），从而缓解SAE。我们的研究结果揭示了小胶质细胞通过cGAS-STING-C1q通路进行突触修剪的新机制，强调了肠道来源的γδ T17细胞迁移至脑膜在SAE中的关键作用，并突出了STING泛素化在调控C1q介导的过度突触修剪中的重要性。