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A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction.

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)-1β (IL-1β) precursor expression, promoted degradation of NLRP3 and IL-1β, 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-1β, 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.

SUBMITTER: Wu CH

PROVIDER: S-EPMC7793731 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction.

Wu Chun-Hsien CH Gan Chin Heng CH Li Lan-Hui LH Chang Jen-Che JC Chen Shin-Tai ST Menon Mridula P MP Cheng Shu-Meng SM Yang Shih-Ping SP Ho Chen-Lung CL Chernikov Oleg V OV Lin Chi-Hung CH Lam Yulin Y Hua Kuo-Feng KF

Frontiers in immunology 20201218

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 IC<sub>50</sub> of ~20 µM. In this study, we synthesized a new anti-inflammatory 4-HAB analogue, F240B, which has an IC<sub>50</sub> of less than 1 µM. F240B dose-dependently induced autophagy by increasing autophagic flux, LC3 speck formation and acidic vesicular organelle formation. F240B inhibite ...[more]

PMID: 33424855

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Project description:Background and purposeIL-1β produced by macrophages via the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, mediates the inflammatory crosstalk between macrophages and adipocytes. In our previous study, (16S,20S,24R)-12β-acetoxy-16,23-epoxy-24,25-dihydroxy-3β-(β-D-xylopyranosyloxy)-9,19-cyclolanost-22(23)-ene (AEDC), a cycloartane triterpenoid isolated from Actaea vaginata (Ranunculaceae), was found to possess anti-inflammatory effect on LPS-treated RAW264.7 macrophages. This study was designed to investigate whether AEDC modulates macrophage-adipocyte crosstalk to alleviate adipose tissue inflammation.Experimental approachThe anti-inflammatory effect of AEDC was evaluated on LPS plus ATP-induced THP-1 macrophages and C57BL/6J mice. The expression of autophagy-related and NLRP3 inflammasome complex proteins was analysed by western blots, immunofluorescence staining and co-immunoprecipitation. The pro-inflammatory cytokines levels were determined by ELISA kits. The adipose tissue inflammation was evaluated by histological analysis and immunohistochemical staining.Key resultsAEDC (5 and 10 μM) activated autophagy, which in turn suppressed the NLRP3 inflammasome activation and IL-1β secretion in THP-1 macrophages. AEDC increased the expression of SIRT3 deacetylase and enhanced its deacetylating activity to reverse mitochondrial dysfunction and activate AMP-activated protein kinase, which together induced autophagy. Moreover, AEDC (10 μM) attenuated macrophage conditioned medium-induced inflammatory responses in adipocytes and blocked THP-1 macrophages migration towards 3T3-L1 adipocytes. In inflammation mice, AEDC (5 and 20 mg·kg-1 ) treatment reduced the levels of pro-inflammatory cytokines in serum and epididymal adipose tissue and reduced macrophage infiltration to alleviate adipose tissue inflammation.Conclusion and implicationsAEDC attenuated the inflammatory crosstalk between macrophages and adipocytes through SIRT3-autophagy-mediated NLRP3 inflammasome inhibition, which might used for the treatment of adipose tissue inflammation-related metabolic disorders.

Dataset Information

A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction.

Publications

A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction.

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