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

Publication date: Available online 26 June 2018
Source:Immunity
Author(s): Anke Di, Shiqin Xiong, Zhiming Ye, R.K. Subbarao Malireddi, Satoshi Kometani, Ming Zhong, Manish Mittal, Zhigang Hong, Thirumala-Devi Kanneganti, Jalees Rehman, Asrar B. Malik
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.

Graphical abstract

Teaser

Potassium efflux is required for NLRP3 inflammasome activation, but the channel mediating the efflux has remained elusive. Di et al. identify the potassium channel TWIK2 as a mediator of potassium efflux and NLRP3 activation in macrophages. Targeting TWIK2 could form the basis for therapeutic approaches in inflammatory injury.


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