NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes
Open accessAbstract
Inflammation in the brain accompanies several high-impact neurological diseases including multiple sclerosis (MS), stroke, and Alzheimer’s disease. Neuroinflammation is sterile, as damage-associated molecular patterns rather than microbial pathogens elicit the response. The inflammasome, which leads to caspase-1 activation, is implicated in neuroinflammation. In this study, we reveal that lysophosphatidylcholine (LPC), a molecule associated with neurodegeneration and demyelination, elicits NLRP3 and NLRC4 inflammasome activation in microglia and astrocytes, which are central players in neuroinflammation. LPC-activated inflammasome also requires ASC (apoptotic speck containing protein with a CARD), caspase-1, cathepsin-mediated degradation, calcium mobilization, and potassium efflux but not caspase-11. To study the physiological relevance, Nlrc4−/− and Nlrp3−/− mice are studied in the cuprizone model of neuroinflammation and demyelination. Mice lacking both genes show the most pronounced reduction in astrogliosis and microglial accumulation accompanied by decreased expression of the LPC receptor G2A, whereas MS patient samples show increased G2A. These results reveal that NLRC4 and NLRP3, which normally form distinct inflammasomes, activate an LPC-induced inflammasome and are important in astrogliosis and microgliosis.
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NLRC4 is expressed highly in astrocytes and microglia and is necessary for the secretion of IL-1β in both cell types after acute demyelination with LPC.
“NLRC4 is expressed highly in astrocytes and microglia and is necessary for the secretion of IL-1β in both cell types after acute demyelination with LPC [332] and may be important for cuprizone-mediated demyelination as well.”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [332]
The Results sections on NLRC4 expression and LPC-induced IL-1β secretion report abundant NLRC4 in astrocytes, lower expression in microglia, and reduced secretion from both cell types when NLRC4 is absent. However, secretion was measured in isolated mouse cells stimulated with LPC, not in both cell types after acute demyelination in vivo; secretion was attenuated rather than abolished. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe activated inflammasome triggers oligodendrocyte death, demyelination, microglia infiltration, and astrocyte activation in the cuprizone model; knockout of IL-18, NLRP3, NLRC4, and Casp-1 in mice yields less severe demyelination after cuprizone treatment.
“The activated inflammasome triggers oligodendrocyte death, demyelination, microglia infiltration, and astrocyte activation in the cuprizone model; knockout of IL-18, NLRP3, NLRC4, and Casp-1 in mice yields less severe demyelination after cuprizone treatment [244, 332].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [332]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredNLRP3 and NLRC4 knockout reduces microglia and astrocyte numbers and attenuates demyelination during cuprizone treatment.
“NLRP3 and NLR Family CARD Domain Containing (NLRC)4, another inflammasome sensor [330], knockout reduces microglia and astrocyte numbers and attenuates demyelination during cuprizone treatment [244, 331, 332].”
From Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination (2022) · cites this paper as [332]
Inflammasome signaling in the CNS has been reported in microglia, astrocytes, perivascular brain-resident macrophages, oligodendrocytes, endothelial cells, and neurons.
“Inflammasome signaling in the CNS has also been reported in the microglia, the brain’s critical innate immune cells (206), in astrocytes (207), perivascular brain-resident macrophages (208), oligodendrocytes (209), endothelial cells (210), as well as in neurons (211).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [207]
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- Authors
- Freeman, L., Guo, H., David, C. N., Brickey, W. J., Jha, S., & Ting, J. P.-Y.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Jha, Sushmita
- Ting, Jenny P.-Y.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2017-04-12
- Volume
- 214
- Issue
- 5
- Pages
- 1351-1370
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC5413320
- OpenAlex
- W2605685784
- Cited by
- 397
- References
- 98
- Citations by year
- 2026: 23 · 2025: 45 · 2024: 48 · 2023: 54 · 2022: 57 · 2021: 60 · 2020: 45 · 2019: 34 · 2018: 23 · 2017: 7
- FWCI
- 12.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Multiple Sclerosis Society (CA-1053-A-8, RG-1785E)
- National Institutes of Health (R37-AI029564, U19AI109965, T32-AIO7273)
- 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 › Immune Response and Inflammation
- Keywords
- NLRC4, NLRP3 inflammasome, lysophosphatidylcholine, neuroinflammation, microglia, astrocytes, caspase-1, ASC, calcium mobilization, potassium efflux, cuprizone demyelination, multiple sclerosis, astrocyte activation, microglial activation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Astrocytes, Calcium-Binding Proteins, Cuprizone, Disease Models, Animal, Inflammation, Lysophosphatidylcholines, Male, Mice, Inbred C57BL, Microglia, Mice, Knockout, Apoptosis Regulatory Proteins, Mice, Inflammasomes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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