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cGAS/STING Pathway Activation Contributes to Delayed Neurodegeneration in Neonatal Hypoxia-Ischemia Rat Model: Possible Involvement of LINE-1
Open accessAbstract
cGAS is a sensor of cytosolic DNA and responds equally to exogenous and endogenous DNA. After recognition of cytosolic dsDNA or ssDNA, cGAS synthesizes the second messenger 2'3'-cGAMP, which then binds to and activates stimulator of interferon genes (STING). STING plays an essential role in responding to pathogenic DNA and self-DNA in the context of autoimmunity. In pathologic conditions, such as stroke or hypoxia-ischemia (HI), DNA can gain access into the cytoplasm of the cell and leak from the dying cells into the extracellular environment, which potentially activates cGAS/STING. Recent in vivo studies of myocardial ischemia, traumatic brain injury, and liver damage models suggest that activation of cGAS/STING is not only a side-effect of the injury, but it can also actively contribute to cell death and apoptosis. We found, for the first time, that cGAS/STING pathway becomes activated between 24 and 48 h after HI in a 10-day-old rat model. Silencing STING with siRNA resulted in decreased infarction area, reduced cortical neurodegeneration, and improved neurobehavior at 48 h, suggesting that STING can contribute to injury progression after HI. STING colocalized with lysosomal marker LAMP-1 and blocking STING reduced the expression of cathepsin B and decreased the expression of Bax and caspase 3 cleavage. We observed similar protective effects after intranasal treatment with cGAS inhibitor RU.521, which were reversed by administration of STING agonist 2'3'-cGAMP. Additionally, we showed that long interspersed element 1 (LINE-1) retrotransposon, a potential upstream activator of cGAS/STING pathway was induced at 48 h after HI, which was evidenced by increased expression of ORF1p and ORF2p proteins and increased LINE-1 DNA content in the cytosol. Blocking LINE-1 with the nucleoside analog reverse-transcriptase inhibitor (NRTI) stavudine reduced infarction area, neuronal degeneration in the cerebral cortex, and reduced the expression of Bax and cleaved caspase 3. Thus, our results identify the cGAS/STING pathway as a potential therapeutic target to inhibit delayed neuronal death after HI.
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“Retrotransposon-derived eccDNA ( Figure 2a ) and dsRNA ( Figure 2b ) can initiate an antiviral response through their detection by the cytosolic DNA–sensing pathway mediated by cGAS-STING and nucleic acid–sensing Toll-like receptors (TLRs), as well as viral RNA sensors such as retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated protein 5 (MDA5, a RIG-I-like receptor),”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Gamdzyk et al. 2020
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1 retracted
RETRACTED ARTICLE: Role of Glibenclamide in Brain Injury After Intracerebral Hemorrhage
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Self-citationRetractedCyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway
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Cyclic GMP-AMP Is an Endogenous Second Messenger in Innate Immune Signaling by Cytosolic DNA
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Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing
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Hu, X., Zhang, H., Zhang, Q., Yao, X. X., Ni, W., & Zhou, K. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02602-y · Cited by 271
Ding, R., Li, H., Liu, Y., Ou, W., Zhang, X., Chai, H., Huang, X., Yang, W., & Wang, Q. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02511-0 · Cited by 246
mtDNA-STING Axis Mediates Microglial Polarization via IRF3/NF-κB Signaling After Ischemic Stroke
Kong, L., Li, W., Chang, E., Wang, W., Shen, N., Xu, X., Wang, X., Zhang, Y., Sun, W., Hu, W., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.860977 · Cited by 191
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Jiang, G.-L., Yang, X., Zhou, H., Long, J., Liu, B., Zhang, L.-M., & Lü, D. (2021) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2021.03.010 · Cited by 132
Metadata
- Authors
- Gamdzyk, M., Doycheva, D. M., Araujo, C., Ocak, U., Luo, Y., Tang, J., & Zhang, J. H.
- Affiliations
- Loma Linda University (US)
- Loma Linda University Medical Center (US)
- Corresponding author
- Zhang, John H.
- Venue
- Molecular Neurobiology
- Published
- 2020-04-06
- Volume
- 57
- Issue
- 6
- Pages
- 2600-2619
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC7260114
- OpenAlex
- W3014215372
- Cited by
- 127
- References
- 84
- Citations by year
- 2026: 20 · 2025: 23 · 2024: 28 · 2023: 22 · 2022: 24 · 2021: 9 · 2020: 1
- FWCI
- 13.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Neurobiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS104083)
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal and fetal brain pathology
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- cGAS-STING pathway, hypoxia-ischemia, neonatal brain injury, delayed neuronal death, LINE-1 retrotransposons, cytosolic DNA sensing, 2'-3'-cGAMP, stavudine, cathepsin B, Bax, caspase-3, neuroprotection
- MeSH terms
- STING Protein, Animals, Cathepsin B, Disease Models, Animal, Membrane Proteins, Nerve Degeneration, Nucleotides, Cyclic, Nucleotidyltransferases, Signal Transduction, Cell Death, Long Interspersed Nucleotide Elements, Gene Silencing, Hypoxia-Ischemia, Brain, RNA, Small Interfering, Adaptor Proteins, Signal Transducing, bcl-2-Associated X Protein, Rats, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 1
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