LRRC8A is essential for hypotonicity-, but not for DAMP-induced NLRP3 inflammasome activation

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Tessa Swanton
  • Lucy Morris
  • Lina El-Sharkawy
  • James Cook
  • Arthur Yu Shi
  • James Beswick
  • Neil Humphreys
  • David Brough


The NLRP3 inflammasome is a multi-molecular protein complex that converts inactive cytokine precursors into active forms of IL-1β and IL-18. The NLRP3 inflammasome is frequently associated with the damaging inflammation of non-communicable disease states and is considered an attractive therapeutic target. However, there is much regarding the mechanism of NLRP3 activation that remains unknown. Chloride efflux is suggested as an important step in NLRP3 activation, but which chloride channels are involved is still unknown. We used chemical, biochemical, and genetic approaches to establish the importance of chloride channels in the regulation of NLRP3 in murine macrophages. Specifically, we identify LRRC8A, an essential component of volume-regulated anion channels (VRAC), as a vital regulator of hypotonicity-induced, but not DAMP-induced, NLRP3 inflammasome activation. Although LRRC8A was dispensable for canonical DAMP-dependent NLRP3 activation, this was still sensitive to chloride channel inhibitors, suggesting there are additional and specific chloride sensing and regulating mechanisms controlling NLRP3.

Bibliographical metadata

Original languageEnglish
Article numbere59704
Issue number9
Publication statusPublished - 20 Nov 2020

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