A Synthetic Small Molecule F240B Decreases NLRP3 Inflammasome Activation by Autophagy Induction
Authors: Shin-Tai Chen
Shih-Ping Yang
Oleg V Chernikov
Chun-Hsien Wu
Chi-Hung Lin
Lan-Hui Li
Mridula P Menon
Chen-Lung Ho
Yulin Lam
Kuo-Feng Hua
Jen-Che Chang
Chin Heng Gan
Shu-Meng Cheng
Journal: Frontiers in Immunology (2020)
Discipline: IMMUNOLOGY
Keywords: NLRP3 inflammasome; autophagy; conjugated polyenes; mitochondria; peritonitis.
Affiliations: Division of Cardiology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan., Department of Chemistry, National University of Singapore, Singapore, Singapore., Department of Laboratory Medicine, Linsen, Chinese Medicine and Kunming Branch, Taipei City Hospital, Taipei, Taiwan., Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan., Department of Biotechnology and Animal Science, National Ilan University, Ilan, Taiwan., Division of Wood Cellulose, Taiwan Forestry Research Institute, Taipei, Taiwan., G.B. Elyakov Pacific Institute of Bioorganic Chemistry FEB RAS, Vladivostok, Russia., Department of Biological Science & Technology, National Chiao Tung University, Hsinchu, Taiwan., Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.

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. 

Retracted: No

PubPeer comments:
 Figure 5E: Actin loading control does not match with p-JNK1 2 ![file] , 
 Could the authors please clarify what they mean by * typographical error * when referring Fig.5E shown in #1 ? From my point of view the mismatching number of lanes is the problem here. **CORRECTION** *In the original article, there was a mistake in Figures 5E and 8E as published. We found typographical errors in Figures 5E and 8E. The corrected Figures 5E and 8E appears below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.* https: www.frontiersin.org articles 10.3389 fimmu.2021.738591 full ,