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Cited by 187Inflammasome and immune disordersNeuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research Studies

Inhibition of the NLRP3-inflammasome prevents cognitive deficits in experimental autoimmune encephalomyelitis mice via the alteration of astrocyte phenotype

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Hou, Baohua, Zhang, Yahui, Liang, Peiyu, He, Yuan, Peng, Biwen, Liu, Wanhong, Han, Song, Yin, Jun +1 more·2020·Cell Death & Disease
DOI 10.1038/s41419-020-2565-2PMC PMC7229224
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Abstract

Multiple sclerosis (MS) is a chronic disease that is characterized by demyelination and axonal damage in the central nervous system. Cognitive deficits are recognized as one of the features of MS, and these deficits affect the patients’ quality of life. Increasing evidence from experimental autoimmune encephalomyelitis (EAE), the animal model of MS, has suggested that EAE mice exhibit hippocampal impairment and cognitive deficits. However, the underlying mechanisms are still unclear. The NLRP3 inflammasome is a key contributor to neuroinflammation and is involved in the development of MS and EAE. Activation of the NLRP3 inflammasome in microglia is fundamental for subsequent inflammatory events. Activated microglia can convert astrocytes to the neurotoxic A1 phenotype in a variety of neurological diseases. However, it remains unknown whether the NLRP3 inflammasome contributes to cognitive deficits and astrocyte phenotype alteration in EAE. In this study, we demonstrated that severe memory deficits occurred in the late phase of EAE, and cognitive deficits were ameliorated by treatment with MCC950, an inhibitor of the NLRP3 inflammasome. In addition, MCC950 alleviated hippocampal pathology and synapse loss. Astrocytes from EAE mice were converted to the neurotoxic A1 phenotype, and this conversion was prevented by MCC950 treatment. IL-18, which is the downstream of NLRP3 inflammasome, was sufficient to induce the conversion of astrocytes to the A1 phenotype through the NF-κB pathway. IL-18 induced A1 type reactive astrocytes impaired hippocampal neurons through the release of complement component 3 (C3). Altogether, our present data suggest that the NLRP3 inflammasome plays an important role in cognitive deficits in EAE, possibly via the alteration of astrocyte phenotypes. Our study provides a novel therapeutic strategy for hippocampal impairment in EAE and MS.

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  • NLRP3 inflammasome activation and subsequent secretion of IL-18 and IL-1β from microglia drives astrocytes into the neurotoxic reactive state, which induces upregulation of the secretion of complement protein C3 and results in lower synapse numbers.

    “Currently, published studies suggest that NLRP3 inflammasome activation and subsequent secretion of IL-18 and IL-1β from microglia drives astrocytes into the neurotoxic reactive state, which induces upregulation of the secretion of the complement protein C3 and results in lower synapse numbers [180, 189–191].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [191]

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Cited by

Sorted by citations

Authors
Hou, B., Zhang, Y., Liang, P., He, Y., Peng, B., Liu, W., Han, S., Yin, J., & He, X.
Affiliations
Wuhan University (CN)
Corresponding author
  • Yin, Jun
  • He, Xiaohua
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2020-05-15
Volume
11
Issue
5
Pages
377-377
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-020-2565-2
PMC
PMC7229224
OpenAlex
W3025918268
Cited by
187
References
9
Citations by year
2026: 17 · 2025: 32 · 2024: 44 · 2023: 31 · 2022: 38 · 2021: 19 · 2020: 5
FWCI
7.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (TFJC2018001, 2017CFA017, 81100594, TFLC2018001)
  • Natural Science Foundation of Hubei Province (2017CFA017)
  • Wuhan University (TFLC2018001, TFJC2018001)
  • Wuhan Science and Technology Project (2019020701011444)
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 › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
NLRP3 inflammasome, experimental autoimmune encephalomyelitis, multiple sclerosis, cognitive impairment, MCC950, IL-18, NF-κB signaling, complement C3, hippocampal neurons, synaptic loss, neuroinflammation, microglia
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Astrocytes, Central Nervous System, Cognition, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Mice, Inbred C57BL, Phenotype, Microglia, Inflammasomes, Cognitive Dysfunction

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