A self-perpetuating neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome axis drives neuronal pyroptosis and cognitive impairment after traumatic brain injury.

Overview

1. Department of Neurosurgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
2. Department of Microbiology and Immunology, Shantou University Medical College, Shantou, Guangdong, China
3. 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/GSDMD-dependent pyroptosis; ethidium bromide-mediated mtDNA depletion reversed each pyroptotic marker. Within the first 0.5–3 h post-injury, activated GSDMD N-terminal fragments (GSDMD-NT) translocated to mitochondria, disrupted mitochondrial membrane potential (ΔΨm) and promoted further mtDNA leakage; CRISPR knockout of GSDMD, but not of Bax, prevented this injury-induced mitochondrial dysfunction. Delayed pharmacological inhibition of caspase-1 (VX-765 applied 6 h after injury, after the first wave) selectively suppressed a discrete second wave of cytosolic mtDNA release at 9–12 h and attenuated late-phase LDH release, providing direct experimental evidence for a self-perpetuating second wave of mtDNA-driven AIM2 activation.

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

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• 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/Supplementary Material. Further inquiries can be directed to the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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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://doi.org/10.3389/fimmu.2026.1867920

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