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 () and Jiancheng Zhang ()
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Yuming Wu: Huazhong University of Science and Technology
Yujing Zhang: Huazhong University of Science and Technology
Yuan Yu: Huazhong University of Science and Technology
Xin Wang: Huazhong University of Science and Technology
Zifan Zhen: Huazhong University of Science and Technology
Yin Yuan: Huazhong University of Science and Technology
Bing Xie: Huazhong University of Science and Technology
Mengqi Han: Huazhong University of Science and Technology
Mengyuan Wang: Huazhong University of Science and Technology
Xinyu Zhang: Huazhong University of Science and Technology
Xueqiang Sun: Huazhong University of Science and Technology
Xiaoyue Wen: Huazhong University of Science and Technology
Kenji Hashimoto: Chiba University Center for Forensic Mental Health
You Shang: Huazhong University of Science and Technology
Shiying Yuan: Huazhong University of Science and Technology
Jiancheng Zhang: Huazhong University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62181-3

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