Author | Moraes, Carolina A. | |
Author | Hottz, Eugenio D. | |
Author | Ornellas, Débora dos Santos | |
Author | Adesse, Daniel | |
Author | Azevedo, Carolina T. de | |
Author | d'Avila, Joana C. | |
Author | Zaverucha-do-Valle, Camila | |
Author | Maron-Gutierrez, Tatiana | |
Author | Barbosa, Helene Santos | |
Author | Bozza, Patricia Torres | |
Author | Bozza, Fernando Augusto | |
Access date | 2023-04-14T01:43:06Z | |
Available date | 2023-04-14T01:43:06Z | |
Document date | 2023 | |
Citation | MORAES, Carolina A. et al. Microglial NLRP3 Inflammasome Induces Excitatory Synaptic Loss Through IL-1β-Enriched Microvesicle Release: Implications for Sepsis-Associated Encephalopathy. Molecular Neurobiology, v. 60, n. 2, p. 481-494, Feb. 2023. | en_US |
ISSN | 0893-7648 | en_US |
URI | https://www.arca.fiocruz.br/handle/icict/57775 | |
Description | Ethics Approval The Animal Welfare Committee of the Oswaldo Cruz Foundation (CEUA/FIOCRUZ) approved and covered (015/2015) the experiments in this study. The procedures described in this study were according to the local guidelines and guidelines published in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The study is reported in accordance with the ARRIVE guidelines for reporting experiments involving animals. | en_US |
Sponsorship | This work was supported by the National Institute of Science and Technology (CNPq), the Rio de Janeiro State Research Supporting Foundation (FAPERJ), and the Coordination for the Improvement of Higher Education Personnel (CAPES). | en_US |
Language | eng | en_US |
Publisher | Humana Press | en_US |
Rights | restricted access | |
Title | Microglial NLRP3 Inflammasome Induces Excitatory Synaptic Loss Through IL‑1β‑Enriched Microvesicle Release: Implications for Sepsis‑Associated Encephalopathy | en_US |
Type | Article | |
DOI | 10.1007/s12035-022-03067-z | |
Abstract | 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. | en_US |
Affilliation | Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Federal University of Juiz de Fora. Department of Biochemistry. Laboratory of Immunothrombosis. Juiz de Fora, MG, Brazil. | en_US |
Affilliation | Federal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Laboratory of Molecular and Cellular Physiology. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Structural Biology. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Inflammation. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil / Iguaçu University. Laboratory of Pre-Clinical Research. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Evandro Chagas National Institute of Infectious Diseases. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Federal University of Rio de Janeiro. Carlos Chagas Filho Biophysics Institute. Laboratory of Molecular and Cellular Physiology. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Oswaldo Cruz Institute. Laboratory of Immunopharmacology. Rio de Janeiro, RJ, Brazil. | en_US |
Affilliation | Oswaldo Cruz Foundation. Evandro Chagas National Institute of Infectious Diseases. Rio de Janeiro, RJ, Brazil / D'Or Institute for Research and Education. Rio de Janeiro, RJ, Brazil. | en_US |
Subject | Microglia | en_US |
Subject | Microvesicles | en_US |
Subject | NLRP3 inflammasome | en_US |
Subject | Sepsis | en_US |
Subject | Synapse loss | en_US |
e-ISSN | 1559-1182 | |
Embargo date | 31-12-2030 | |