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Cited by 29Neuroinflammation and Neurodegeneration MechanismsSepsis Diagnosis and TreatmentBacterial Infections and Vaccines

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

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Wu, Yuming, Zhang, Yujing, Yu, Yuan, Wang, Xin, Zhen, Zifan, Yuan, Yin, Xie, Bing, Han, Mengqi, Wang, Mengyuan, Zhang, Xinyu, Sun, Xueqiang, Wen, Xiaoyue, Hashimoto, Kenji, Shang, You, Yuan, Shiying, Zhang, Jiancheng·2025·Nature Communications
DOI 10.1038/s41467-025-62181-3PMC PMC12287374

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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. 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.

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Metadata

Authors
Wu, Y., Zhang, Y., Yu, Y., Wang, X., Zhen, Z., Yuan, Y., Xie, B., Han, M., Wang, M., Zhang, X., Sun, X., Wen, X., Hashimoto, K., Shang, Y., Yuan, S., & Zhang, J.
Affiliations
  • Huazhong University of Science and Technology (CN)
  • Chiba University (JP)
  • Wuhan Union Hospital (CN)
Corresponding author
  • Shang, You
  • Yuan, Shiying
  • Zhang, Jiancheng
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-07-23
Volume
16
Issue
1
Pages
6779-6779
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-62181-3
PMC
PMC12287374
OpenAlex
W4412591989
Cited by
29
References
8
Citations by year
2026: 25 · 2025: 4
FWCI
10.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by-nc-nd)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (82272231, 82472223, 82402568, 82302471, 82071480)
  • Ministry of Science and Technology of the People's Republic of China (2021YFC2500801)
  • Huazhong University of Science and Technology
  • Tongji University
  • National Science and Technology Major Project
  • National Key Research and Development Program of China (2021YFC2500801)
  • Tongji Medical College, Huazhong University of Science and Technology
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Critical Care and Intensive Care Medicine › Sepsis Diagnosis and Treatment
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
sepsis-associated encephalopathy, IL-17A, 4-octyl itaconate, hippocampal synapses
MeSH terms
STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Animals, Cell Movement, Hippocampus, Intestine, Small, Male, Membrane Proteins, Mice, Inbred C57BL, Nucleotidyltransferases, Synapses, Receptors, Antigen, T-Cell, gamma-delta, Microglia, Sepsis, Interleukin-17, Mice, Ubiquitination

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