Differential role of pannexin-1/ATP/P2X7 axis in IL-1β release by human monocytes

Research output: Contribution to journalArticle

Abstract

IL-1β release is integral to the innateimmunesystem.The release ofmature IL-1βdepends on 2 regulated events: the de novo induction of pro-IL-1β, generally via NF-κB-dependent transduction pathways; and the assembly and activation of the NLRP3 inflammasome. This latter step is reliant on active caspase-1, pannexin-1, and P2X7 receptor activation. Pathogen-associated molecular patterns in gram-positive and gram-negative bacteria activate IL-1β release from immune cells via TLR2 and TLR4 receptors, respectively. We found that pro-IL-1β and mature IL-1β release fromhumanmonocytes is stimulated by the TLR2 agonists Pam3CSK4 or FSL-1, as well as the TLR4agonist LPSin the absence of additionalATP.TLR2agonists requiredpannexin-1 and P2X7 receptor activation to stimulate IL-1β release. In contrast, IL-1β release stimulated by the TLR4 agonist LPS is independent of both pannexin-1 and P2X7 activation. In the absenceof exogenousATP,P2X7 activationrequires endogenousATPrelease, which occurs in some cells via pannexin-1. In line with this, we found that LPS-stimulated human monocytes released relatively low levels of ATP, whereas cells stimulated with TLR2 agonists released high levels of ATP. These findings suggest that in humanmonocytes, both TLR2 and TLR4 signaling induce pro-IL-1β expression, but themechanismbywhich they activate caspase-1diverges at the level of thepannexin-1/ATP/P2X7 axis.

Details

Authors
  • Katarzyna Parzych
  • Anna V. Zetterqvist
  • William R. Wright
  • Nicholas S Kirkby
  • Jane A Mitchell
  • Mark J. Paul-Clark
Organisations
External organisations
  • Imperial College London
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • Inflammasome, Innate immunity, Potassium channels, Toll-like receptors
Original languageEnglish
Pages (from-to)2439-2445
Number of pages7
JournalFASEB Journal
Volume31
Issue number6
Publication statusPublished - 2017 Jun 1
Publication categoryResearch
Peer-reviewedYes