Luteolin prevents THP-1 macrophage pyroptosis by suppressing ROS production via Nrf2 activation

Chem Biol Interact. 2021 Aug 25:345:109573. doi: 10.1016/j.cbi.2021.109573. Epub 2021 Jul 1.

Abstract

Pyroptosis plays an important role in the pathogenesis of numerous infectious, autoimmune, and inflammatory diseases, which makes it a promising target for intervention. In this study, the effect of luteolin on pyroptosis and the underlying mechanism were investigated using the canonical NLRP3 inflammasome in THP-1 macrophages induced by LPS/ATP. The results showed that luteolin exhibited a potent preventive effect on THP-1 macrophage pyroptosis, as evidenced by the increase in cell viability and the decrease in LDH release. Moreover, luteolin was found to significantly reduce the expression of NLRP3, pro-CASP-1 and CASP-1, which are the key components of NLRP3 inflammasome, as well as the expression of N-GSDMD and IL-1β, and we proved that the inhibition of luteolin on NLRP3 inflammasome activation is ROS-dependent. Furthermore, it was demonstrated that luteolin promoted Nrf2 nuclear translocation, thereby increasing the expression of HO-1 that reduces ROS production, while the anti-pyroptotic effect of luteolin was reversed by a specific Nrf2 inhibitor. Additionally, luteolin inhibited NF-κB p65 phosphorylation and nuclear translocation. In summary, we conclude that luteolin prevents THP-1 macrophage pyroptosis by suppressing ROS production via Nrf2 activation as well as NF-κB inactivation. These results support luteolin as a potential bioactive chemical against pyroptosis-related inflammatory diseases.

Keywords: Luteolin; NF-κB; NLRP3 inflammasome; Nrf2; Pyroptosis; ROS.

MeSH terms

  • Cell Line
  • Gene Expression Regulation / drug effects
  • Humans
  • Inflammasomes / metabolism
  • Luteolin / pharmacology*
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • NF-E2-Related Factor 2 / metabolism*
  • NF-kappa B / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Pyroptosis / drug effects*
  • Reactive Oxygen Species / metabolism*

Substances

  • Inflammasomes
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Reactive Oxygen Species
  • Luteolin