Small intestinal γδ T17 cells promote SAE through STING/C1q-induced microglial synaptic pruning in male mice
Yuming Wu, Yujing Zhang, Yuan Yu, Xin Wang, Zifan Zhen, Yin Yuan, Bing Xie, Mengqi Han, Mengyuan Wang, Xinyu Zhang, Xueqiang Sun, Xiaoyue Wen, Kenji Hashimoto, You Shang, Shiying Yuan, Jiancheng Zhang
Abstract
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 in male mice. 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 suggest a potential 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. Sepsis-associated encephalopathy (SAE) is a severe and often fatal consequence of sepsis. Here authors show in a mouse model of sepsis that γδ T17 cells, migrating from the small intestine to the meninges, play a pathological role via activation of STING in microglia, leading to an increase in C1q-tagged synapses, which are subsequently pruned.