AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment
Open accessAbstract
Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis 1-4. We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.
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AIM2 inflammasome has a role in normal brain development.
“Recently, AIM2 inflammasome has been shown to have a role in the normal brain development.”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [205]
AIM2 inflammasome is activated in the presence of DNA damage that occurs at high levels during infections, trauma, and neurodevelopment upon massive cell death.
“It gets activated in presence of DNA damage that occurs at high levels during infections, trauma, but also neurodevelopment upon massive cell death (205).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [205]
Under physiological conditions, AIM2 inflammasome is activated during neurodevelopment and contributes to CNS physiology acting through gasdermin-D regulation, and not through IL-1β and IL-18 production.
“Under physiological conditions, AIM2 inflammasome is activated during neurodevelopment and contributes to CNS physiology acting through gasdermin-D regulation, and not through IL-1β and IL-18 production (205).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [205]
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The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology
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“Elevated plus maze—EPM was used to investigate anxiety in mice and was performed as described previously (Lammert et al., 2020).”
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- Authors
- Lammert, C. R., Frost, E. L., Bellinger, C. E., Bolte, A. C., McKee, C. A., Hurt, M. E., Paysour, M. J., Ennerfelt, H. E., & Lukens, J. R.
- Affiliations
- University of Virginia (US)
- Corresponding author
- Lukens, John R.
- ORCID
- Venue
- Nature
- Published
- 2020-04-08
- Volume
- 580
- Issue
- 7805
- Pages
- 647-652
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7788527
- OpenAlex
- W3016091053
- Cited by
- 223
- References
- 40
- Citations by year
- 2026: 17 · 2025: 34 · 2024: 46 · 2023: 36 · 2022: 47 · 2021: 30 · 2020: 13
- FWCI
- 10.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL136314)
- National Institute of General Medical Sciences (T32GM008328, T32GM008136, T32GM007267, T32GM139787)
- National Institute of Allergy and Infectious Diseases (T32AI007496)
- National Institute of Neurological Disorders and Stroke (R01NS106383)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- AIM2 inflammasome, brain development, DNA damage, gasdermin D, pyroptosis, anxiety-like behavior, neuronal cell death, genotoxic stress, innate immune surveillance, double-stranded DNA, brain maturation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Gasdermins, Animals, Animals, Newborn, Anxiety, Behavior, Animal, Brain, DNA Damage, DNA-Binding Proteins, Male, Mutation, Neurons, Cell Death, Maze Learning, Caspase 1, Phosphate-Binding Proteins, Intracellular Signaling Peptides and Proteins, Mice, CARD Signaling Adaptor Proteins, Inflammasomes
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