The two pore potassium channel THIK‐1 regulates NLRP3 inflammasome activation

Abstract

The NLRP3 (NLR family, pyrin domain containing 3) inflammasome is a multi‐protein complex responsible for the activation of caspase‐1 and the subsequent cleavage and activation of the potent proinflammatory cytokines IL‐1β and IL‐18, and pyroptotic cell death. NLRP3 is implicated as a driver of inflammation in a range of disorders including neurodegenerative diseases, type 2 diabetes, and atherosclerosis. A commonly reported mechanism contributing to NLRP3 inflammasome activation is potassium ion (K+) efflux across the plasma membrane. Identification of K+ channels involved in NLRP3 activation remains incomplete. Here, we investigated the role of the K+ channel THIK‐1 in NLRP3 activation. Both pharmacological inhibitors and cells from THIK‐1 knockout (KO) mice were used to assess THIK‐1 contribution to macrophage NLRP3 activation in vitro. Pharmacological inhibition of THIK‐1 inhibited caspase‐1 activation and IL‐1β release from mouse bone‐marrow‐derived macrophages (BMDMs), mixed glia, and microglia in response to NLRP3 agonists. Similarly, BMDMs and microglia from THIK‐1 KO mice had reduced NLRP3‐dependent IL‐1β release in response to P2X7 receptor activation with ATP. Overall, these data suggest that THIK‐1 is a regulator of NLRP3 inflammasome activation in response to ATP and identify THIK‐1 as a potential therapeutic target for inflammatory disease.

The role of Nod-like receptor protein 3 inflammasome activated by ion channels in multiple diseases

“…P2X7, a kind of P2 receptors can be activated by ATP aggregation, which is required for ATP aggregation-induced activation of NLRP3 [ 25 ]. In recent years it has been found that P2X7 may partially regulate K + currents through the two-pore domain K + channels, such as Pore Domain Halothane-Inhibited Potassium Channel 1 (THIK-1) and Two-pore domain Weak Inwardly rectifying K + channel 2 (TWIK-2) [ 26 ] (Fig. 3 ).…”

“…Researchers found that THIK-1 is required for NLRP3-dependent Caspase-1 activation and IL-1β release in response to ATP. By blocking THIK-1, it inhibits the release of Pro-inflammatory cytokine il-1β from the activated microglia, which suggests that THIK-1 may be a therapeutic target for Nervous system inflammation diseases [ 26 , 60 ].…”

Regulation of the two-pore domain potassium channel, THIK-1 and THIK-2, by G protein coupled receptors

“…The THIK-1 (two pore domain halothane-inhibited K + ) channel is a member of K2P channel family, whose mRNA was shown to express in neuronal cells [8,9]. The functional THIK-1 channel is expressed in neuronal cells [10][11][12][13] and shown in microglia [14][15][16]. THIK-1 is reported to regulate the microglial raminification and surveillance, and to contribute to the synapse development and the NLRP3 inflammasome activation [14][15][16].…”

“…The functional THIK-1 channel is expressed in neuronal cells [10][11][12][13] and shown in microglia [14][15][16]. THIK-1 is reported to regulate the microglial raminification and surveillance, and to contribute to the synapse development and the NLRP3 inflammasome activation [14][15][16]. The THIK-1 channel was also suggested to contribute to the apoptosis through irreversibly increasing its K + conductance by caspase-8 dependent truncation of the C-tail [17].…”

Discovery of CVN293, a Brain Permeable KCNK13 (THIK-1) Inhibitor Suitable for Clinical Assessment

“…The role of K + efflux in canonical NLRP3 activation, in response to many stimuli, is well documented, and several ion channels have been suggested to mediate this K + current in microglia. One such channel is encoded by the KCNK13 (K 2P 13.1) gene, which translates to a two-pore forming domain K + channel, also known as THIK-1. , We previously showed that, when N uclear E nriched T ranscript S ort SEQ uencing (NETSseq) is used, KCNK13 is specifically expressed in human microglia and transcript levels increase in microglial nuclei isolated from post-mortem brain tissue from patients with Alzheimer’s disease compared to nonaffected control donors . This observation has been confirmed by a recent study demonstrating a significant increase in RNA and reduction in DNA methylation of KCNK13 in brain tissue from patients with Alzheimer’s and Parkinson’s disease .…”