The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation

Immunity. 2018 Jul 17;49(1):56-65.e4. doi: 10.1016/j.immuni.2018.04.032. Epub 2018 Jun 26.

Abstract

Potassium (K+) efflux across the plasma membrane is thought to be an essential mechanism for ATP-induced NLRP3 inflammasome activation, yet the identity of the efflux channel has remained elusive. Here we identified the two-pore domain K+ channel (K2P) TWIK2 as the K+ efflux channel triggering NLRP3 inflammasome activation. Deletion of Kcnk6 (encoding TWIK2) prevented NLRP3 activation in macrophages and suppressed sepsis-induced lung inflammation. Adoptive transfer of Kcnk6-/- macrophages into mouse airways after macrophage depletion also prevented inflammatory lung injury. The K+ efflux channel TWIK2 in macrophages has a fundamental role in activating the NLRP3 inflammasome and consequently mediates inflammation, pointing to TWIK2 as a potential target for anti-inflammatory therapies.

Keywords: KCNK6; NLRP3 inflammasome; P2X7 receptor; TWIK2; inflammation; potassium channel.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Caspase 1 / deficiency
  • Caspase 1 / metabolism
  • Cell Line
  • Inflammasomes / drug effects
  • Inflammasomes / metabolism*
  • Inflammation / physiopathology*
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides / pharmacology
  • Lung Injury / metabolism
  • Lung Injury / physiopathology
  • Macrophages / metabolism*
  • Macrophages / transplantation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Potassium Channels / drug effects
  • Potassium Channels / metabolism
  • Potassium Channels, Tandem Pore Domain / antagonists & inhibitors
  • Potassium Channels, Tandem Pore Domain / deficiency
  • Potassium Channels, Tandem Pore Domain / metabolism*
  • Quinine / pharmacology
  • RNA, Small Interfering / pharmacology
  • Receptors, Purinergic P2X7 / deficiency
  • Receptors, Purinergic P2X7 / metabolism
  • Sepsis / metabolism
  • Sepsis / physiopathology
  • Signal Transduction / drug effects

Substances

  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Kcnk6 protein, mouse
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Potassium Channels
  • Potassium Channels, Tandem Pore Domain
  • RNA, Small Interfering
  • Receptors, Purinergic P2X7
  • Adenosine Triphosphate
  • Quinine
  • Casp1 protein, mouse
  • Caspase 1