The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins
Abstract
Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β‐amyloid and α‐synuclein trigger microglial NLRP3 activation, leading to caspase‐1 activation and IL‐1β secretion. Both caspase‐1 and IL‐1β contribute to disease progression in the mouse SOD1 G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1 G93A mice microglia do not express NLRP3, and SOD1 G93A protein generated IL‐1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3 ‐GFP gene knock‐in mice that microglia express NLRP3 in SOD1 G93A mice. We show that both aggregated and soluble SOD1 G93A activates inflammasome in primary mouse microglia leading caspase‐1 and IL‐1β cleavage, ASC speck formation, and the secretion of IL‐1β in a dose‐ and time‐dependent manner. Importantly, SOD1 G93A was unable to induce IL‐1β secretion from microglia deficient for Nlrp3 , or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1‐induced microglial IL‐1β secretion. Microglial NLRP3 upregulation was also observed in the TDP‐43 Q331K ALS mouse model, and TDP‐43 wild‐type and mutant proteins could also activate microglial inflammasomes in a NLRP3‐dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1 G93A ‐mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.
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Nlrp3 knockout or pretreatment with a specific NLRP3 inhibitor blocked SOD1G93A protein's ability to induce IL-1β secretion from microglia, indicating some specific pro-inflammatory factors production was NLRP3 dependent.
“Nlrp3 knockout or pretreatment with a specific NLRP3 inhibitor blocked SOD1G93A protein’s ability to induce IL-1β secretion from microglia, indicating some specific pro-inflammatory factors production was NLRP3 dependent.508”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [508]
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- Authors
- Deora, V., Lee, J. D., Albornoz, E. A., McAlary, L., Jagaraj, C. J., Robertson, A. A. B., Atkin, J. D., Cooper, M. A., Schroder, K., Yerbury, J. J., Gordon, R., & Woodruff, T. M.
- Affiliations
- The University of Queensland (AU)
- University of Wollongong (AU)
- Macquarie University (AU)
- Corresponding author
- Woodruff, Trent M.
- ORCID
- Venue
- Glia
- Publisher
- Wiley
- Published
- 2019-10-09
- Volume
- 68
- Issue
- 2
- Pages
- 407-421
- ISSN
- 0894-1491 (ISSN-L)
- 1098-1136
- OpenAlex
- W2979373607
- Cited by
- 245
- References
- 64
- Citations by year
- 2026: 32 · 2025: 27 · 2024: 30 · 2023: 33 · 2022: 39 · 2021: 37 · 2020: 28 · 2019: 1
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Update notices
- erratum (2020-02-28)
- Open access
- closed
- Locations
- Glia (publishedVersion)
- PubMed (publishedVersion)
- Research Online (University of Wollongong) (submittedVersion)
- Figshare (submittedVersion)
- Funders
- Motor Neurone Disease Research Institute of Australia
- National Health and Medical Research Council (APP1082271, APP1084144, APP1086786, APP1105420)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- NLRP3 inflammasome, microglia, amyotrophic lateral sclerosis, SOD1 G93A, IL-1β secretion, caspase-1, neuroinflammation, reactive oxygen species, ATP, MCC950, protein aggregation
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Disease Models, Animal, Humans, Mice, Transgenic, Microglia, Disease Progression, Inflammasomes
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