Chemical mitochondrial uncouplers share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation

Toxicol Appl Pharmacol. 2021 Mar 1:414:115426. doi: 10.1016/j.taap.2021.115426. Epub 2021 Jan 30.

Abstract

Activation of NLRP3 inflammasome is implicated in varieties of pathologies, the aim of the present study is to characterize the effect and mechanism of mitochondrial uncouplers on NLRP3 inflammasome activation by using three types of uncouplers, niclosamide, CCCP and BAM15. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increases of NLRP3 protein and IL-1β mRNA levels in RAW264.7 macrophages and THP-1 derived macrophages. Niclosamide, CCCP and BAM15 inhibited LPS plus ATP-induced increase of NFκB (P65) phosphorylation, and inhibited NFκB (P65) nuclear translocation in RAW264.7 macrophages. Niclosamide and BAM15 inhibited LPS-induced increase of IκBα phosphorylation in RAW264.7 macrophages, and the inhibitory effect was dependent on increased intracellular [Ca2+]i; however, CCCP showed no significant effect on IκBα phosphorylation in RAW264.7 macrophages stimulated with LPS. In conclusion, chemical mitochondrial uncouplers niclosamide, CCCP and BAM15 share common inhibitory effect on NLRP3 inflammasome activation through inhibiting NFκB nuclear translocation.

Keywords: IL-1β; Macrophages; Mitochondrial Uncouplers; NLRP3 Inflammasome.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Active Transport, Cell Nucleus
  • Animals
  • Calcium / metabolism
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone / toxicity
  • Cytokines / genetics
  • Cytokines / metabolism
  • Diamines / toxicity
  • Humans
  • Inflammasomes / agonists*
  • Inflammasomes / metabolism
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • NF-KappaB Inhibitor alpha / metabolism
  • NF-kappa B / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / agonists*
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Niclosamide / toxicity
  • Oxadiazoles / toxicity
  • Phosphorylation
  • Pyrazines / toxicity
  • RAW 264.7 Cells
  • THP-1 Cells
  • Uncoupling Agents / toxicity*

Substances

  • Cytokines
  • Diamines
  • Inflammasomes
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • Oxadiazoles
  • Pyrazines
  • Uncoupling Agents
  • mitochondrial uncoupler BAM15
  • NF-KappaB Inhibitor alpha
  • Carbonyl Cyanide m-Chlorophenyl Hydrazone
  • Niclosamide
  • AMP-Activated Protein Kinases
  • Calcium