A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury.
Overview
- Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
- Department of Microbiology and Immunology, Shantou University Medical College, Shantou, Guangdong, China
- The Department of International Medical Services, the Affiliated Cancer Hospital of Shantou University Medical College, Guangdong, China
Abstract
Introduction: Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide, producing acute neurological deficits and lasting cognitive impairment. Post-injury neuroinflammation is a principal driver of secondary damage and contributes substantially to TBI-induced cognitive dysfunction (TBI-CD), yet the cell-autonomous mechanisms operating within neurons remain incompletely characterised. The AIM2 inflammasome — a cytosolic sensor of double-stranded DNA that drives pro-inflammatory cytokine release and pyroptosis — has been studied primarily in myeloid cells, and its role within neurons after TBI is unclear.
Methods: Here, using a controlled cortical impact (CCI) mouse model, an in vitro mechanical-injury model, AAV-mediated neuron-specific AIM2 knockdown and a comprehensive set of behavioural and molecular assays, we define a neuron-intrinsic, self-perpetuating GSDMD–mtDNA–AIM2 axis that drives neuronal pyroptosis and cognitive decline after TBI.
Results: CCI triggered acute (24 h) AIM2 inflammasome activation specifically in cortical and hippocampal neurons, neuronal pyroptosis and CA3 neuronal loss. AAV-mediated knockdown of AIM2 in hippocampal CA3 neurons significantly reduced neuronal loss in this region and rescued cognitive performance in the Y-maze, novel object recognition and Morris water maze at 14 and 28 days post-injury. Mechanistically, mechanical injury caused early (3–6 h) release of mitochondrial DNA (mtDNA) — but not nuclear DNA — into the neuronal cytosol, where it directly activated the AIM2 inflammasome and engaged caspase-1/
Conclusion: These findings define a self-perpetuating, neuron-intrinsic GSDMD–mtDNA–AIM2 inflammasome–pyroptosis axis as a driver of TBI-CD, and identify neuron-targeted AIM2 silencing as a candidate therapeutic strategy for limiting post-TBI neuroinflammation and cognitive decline.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE226072, at NCBI GEO; found in the text, “Discussion”
Data availability statement
The original contributions presented in the study are included in the article/
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 2, 28 September 2026
- Funding: added Natural Science Foundation of Guangdong Province: 2022A1515012144, 2023A1515012055
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, pages, dates, 11 authors, 5 keywords, 15 MeSH terms, 46 references.
Cite
This paper
Li, T., Huang, S., Zhang, J., Liu, X., Zhu, L., Li, Y., Lin, R., Chen, X., Li, K., Chen, W., & Sheng, J. (2026). A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury. Frontiers in immunology, 17, 1867920. https://
BibTeX
@article{li2026self,
author = {Li, Tian and Huang, Siyu and Zhang, Junjun and Liu, Xueer and Zhu, Lihong and Li, Yue and Lin, Runmin and Chen, Xiaoxuan and Li, Kangsheng and Chen, Weiqiang and Sheng, Jiangtao},
title = {{A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury}},
journal = {Frontiers in immunology},
year = {2026},
month = jun,
volume = {17},
pages = {1867920},
publisher = {Frontiers Media SA},
issn = {1664-3224},
doi = {10.3389/
url = {https://
pmid = {42404904},
pmcid = {PMC13327905}
}
RIS
TY - JOUR
AU - Li, Tian
AU - Huang, Siyu
AU - Zhang, Junjun
AU - Liu, Xueer
AU - Zhu, Lihong
AU - Li, Yue
AU - Lin, Runmin
AU - Chen, Xiaoxuan
AU - Li, Kangsheng
AU - Chen, Weiqiang
AU - Sheng, Jiangtao
TI - A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury
T2 - Frontiers in immunology
J2 - Front Immunol
PY - 2026
DA - 2026/
VL - 17
SP - 1867920
SN - 1664-3224
PB - Frontiers Media SA
DO - 10.3389/
UR - https://
LA - en
ER -
CSL-JSON
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