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.
Copyright © 2018 Elsevier Inc. All rights reserved.
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