A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction.
Front Immunol
; 11: 607564, 2020.
Article
em En
| MEDLINE
| ID: mdl-33424855
ABSTRACT
Conjugated polyenes are a class of widely occurring natural products with various biological functions. We previously identified 4-hydroxy auxarconjugatin B (4-HAB) as anti-inflammatory agent with an IC50 of ~20 µM. In this study, we synthesized a new anti-inflammatory 4-HAB analogue, F240B, which has an IC50 of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibited NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome activation through autophagy induction. In a mechanistic study, F240B inhibited interleukin (IL)-1ß (IL-1ß) precursor expression, promoted degradation of NLRP3 and IL-1ß, and reduced mitochondrial membrane integrity loss in an autophagy-dependent manner. Additionally, F240B inhibited apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization and speck formation without affecting the interaction between NLRP3 and ASC or NIMA-related kinase 7 (NEK7) and double-stranded RNA-dependent kinase (PKR). Furthermore, F240B exerted in vivo anti-inflammatory activity by reducing the intraperitoneal influx of neutrophils and the levels of IL-1ß, active caspase-1, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in lavage fluids in a mouse model of uric acid crystal-induced peritonitis. In conclusion, F240B attenuated the NLRP3 inflammasome through autophagy induction and can be developed as an anti-inflammatory agent in the future.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peritonite
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Autofagia
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Inflamassomos
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Proteína 3 que Contém Domínio de Pirina da Família NLR
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Macrófagos
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Anti-Inflamatórios
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Front Immunol
Ano de publicação:
2020
Tipo de documento:
Article