Microglial NLRP3 Inflammasome Induces Excitatory Synaptic Loss Through IL-1β-Enriched Microvesicle Release: Implications for Sepsis-Associated Encephalopathy.
Animals
Mice
Caspase 1
/ metabolism
Inflammasomes
/ metabolism
Interleukin-1beta
/ metabolism
Lipopolysaccharides
/ pharmacology
Mice, Inbred NOD
Microglia
/ metabolism
NLR Family, Pyrin Domain-Containing 3 Protein
/ metabolism
Reactive Oxygen Species
/ metabolism
Sepsis
/ complications
Sepsis-Associated Encephalopathy
/ metabolism
Microglia
Microvesicles
NLRP3 inflammasome
Sepsis
Synapse loss
Journal
Molecular neurobiology
ISSN: 1559-1182
Titre abrégé: Mol Neurobiol
Pays: United States
ID NLM: 8900963
Informations de publication
Date de publication:
Feb 2023
Feb 2023
Historique:
received:
21
06
2022
accepted:
03
10
2022
pubmed:
25
10
2022
medline:
21
1
2023
entrez:
24
10
2022
Statut:
ppublish
Résumé
Acute cerebral dysfunction is a pathological state common in severe infections and a pivotal determinant of long-term cognitive outcomes. Current evidence indicates that a loss of synaptic contacts orchestrated by microglial activation is central in sepsis-associated encephalopathy. However, the upstream signals that lead to microglial activation and the mechanism involved in microglial-mediated synapse dysfunction in sepsis are poorly understood. This study investigated the involvement of the NLRP3 inflammasome in microglial activation and synaptic loss related to sepsis. We demonstrated that septic insult using the cecal ligation and puncture (CLP) model induced the expression of NLRP3 inflammasome components in the brain, such as NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), caspase-1, and IL-1β. Immunostaining techniques revealed increased expression of the NLRP3 inflammasome in microglial cells in the hippocampus of septic mice. Meanwhile, an in vitro model of primary microglia stimulated with LPS exhibited an increase in mitochondrial reactive oxygen species (ROS) production, NLRP3 complex recruitment, and IL-1β release. Pharmacological inhibition of NLRP3, caspase-1, and mitochondrial ROS all decreased IL-1β secretion by microglial cells. Furthermore, we found that microglial NLRP3 activation is the main pathway for IL-1β-enriched microvesicle (MV) release, which is caspase-1-dependent. MV released from LPS-activated microglia induced neurite suppression and excitatory synaptic loss in neuronal cultures. Moreover, microglial caspase-1 inhibition prevented neurite damage and attenuated synaptic deficits induced by the activated microglial MV. These results suggest that microglial NLRP3 inflammasome activation is the mechanism of IL-1β-enriched MV release and potentially synaptic impairment in sepsis.
Identifiants
pubmed: 36280654
doi: 10.1007/s12035-022-03067-z
pii: 10.1007/s12035-022-03067-z
doi:
Substances chimiques
Caspase 1
EC 3.4.22.36
Inflammasomes
0
Interleukin-1beta
0
Lipopolysaccharides
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Nlrp3 protein, mouse
0
Reactive Oxygen Species
0
IL1B protein, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
481-494Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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