Search

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 50 of ~20 µM. In this study, we synthesized a new anti-inflammatory 4-HAB analogue, F240B, which has an IC 50 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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Wu, Gan, Li, Chang, Chen, Menon, Cheng, Yang, Ho, Chernikov, Lin, Lam and Hua.)

Keywords: NLRP3 inflammasome; conjugated polyenes; autophagy; mitochondria; peritonitis EN NLRP3 inflammasome conjugated polyenes autophagy mitochondria peritonitis 1 3 3 12/17/21 20211215 NES 211215 In the original article, there was a mistake in Figures 5E and 8E as published. In addition, in Figures 8E of the original manuscript, the Western blot image of input NLRP3 included a non-specific band (far left band), making it looks like a mismatch between input NLRP3 and input PKR. [Extracted from the article]