Bongkrekic acid induced neutrophil extracellular traps via p38, ERK, PAD4, and P2X1-mediated signaling

Toxicol Appl Pharmacol. 2021 Jul 15:423:115580. doi: 10.1016/j.taap.2021.115580. Epub 2021 May 19.

Abstract

Bongkrekic acid (BKA) produced by pseudomonas cocovenenans is a deadly toxin, and is mainly found in spoiled or fermented foods. However, less is known on its immunotoxicity. Neutrophil extracellular traps (NETs) are a novel effector mechanism of neutrophils against invading pathogens, but excessive NETs also contribute to tissue damage. This study aimed to investigate NET formation triggered by BKA in murine neutrophils, and describe its characteristics and potential mechanisms. Our results showed that BKA triggered NET formation via co-localization of DNA and histone or MPO by immunostaining. Moreover, BKA-triggered NET formation was dose- and time-dependent via NET quantification based on Picogreen-derived fluorescence intensities. Furthermore, BKA increased ROS production in neutrophils. Pharmacological inhibition indicated that BKA-triggered NET formation was associated with ROS-p38 and -ERK signaling pathways, but independent on NADPH oxidase. Besides, PAD4 and P2X1 receptor also mediated BKA-triggered NET formation. To our knowledge, all these findings provide for the first time an initial understanding of BKA on innate immunity, which might be helpful for further investigation on BKA immunotoxicity.

Keywords: Bongkrekic acid; Immunotoxicity; Neutrophil extracellular traps; Signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / toxicity
  • Bongkrekic Acid / toxicity*
  • Dose-Response Relationship, Drug
  • Extracellular Traps / drug effects
  • Extracellular Traps / metabolism*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Protein-Arginine Deiminase Type 4 / metabolism*
  • Receptors, Purinergic P2X1 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Anti-Bacterial Agents
  • Receptors, Purinergic P2X1
  • Bongkrekic Acid
  • p38 Mitogen-Activated Protein Kinases
  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse