Understanding the role of the THIK-1 Potassium Channel in NLRP3 inflammasome activation.

  • Samuel Drinkall

Student thesis: Phd


The NLRP3 inflammasome is a multi-protein complex responsible for the activation of caspase-1 and the subsequent cleavage and activation of the potent inflammatory cytokines IL-1β and IL-18, and pyroptotic cell death. NLRP3 is implicated as a driver of inflammation in a range of diseases 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 the K+ channels involved in NLRP3 activation remains incomplete. In this thesis, the role of the K+ channel THIK-1 in NLRP3 activation was investigated. Pharmacological inhibitors, siRNA-induced THIK-1 gene knockdown and cells from THIK-1 knockout mice were used to assess THIK-1 contribution to macrophage, monocyte and microglial NLRP3 activation in vitro. Pharmacological inhibition of the THIK-1 K+ channels inhibited caspase-1 activation in mouse bone- marrow derived macrophages (BMDMs), mixed glia, and microglia in response to NLRP3 agonists. Similarly, BMDMs and microglia from THIK-1 knockout mice had reduced NLRP3-dependent IL-1β release in response to P2X7 receptor activation with ATP. We further identified that K+ efflux was required for caspase-1 activation, but formation of the ASC speck still occurred in the presence of K+ channel inhibitors. In addition, THIK-1 mRNA levels were found to be elevated in post-mortem brain tissue from Alzheimer's and Parkinson's disease patients. Overall, these data suggest that the THIK- 1 K+ channel is a regulator of NLRP3 inflammasome activation in response to ATP and identify THIK- 1 as a potential therapeutic target for inflammatory disease.
Date of Award31 Dec 2022
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorCatherine Lawrence (Supervisor), David Brough (Supervisor) & Michael Harte (Supervisor)

Cite this