Pro-inflammatory Ca ++-activated K + channels are inhibited by hydroxychloroquine

Sci Rep. 2017 May 15;7(1):1892. doi: 10.1038/s41598-017-01836-8.

Abstract

Antimalarials have demonstrated beneficial effects in Systemic Lupus Erithematosus and Rheumatoid Arthritis. However, the mechanisms and the molecular players targeted by these drugs remain obscure. Although hydroxychloroquine (HCQ) is a known ion channel inhibitor, this property has not been linked to its anti-inflammatory effects. We aimed to study whether HCQ inhibits pro-inflammatory ion channels. Electrophysiology experiments demonstrated that HCQ inhibited Ca++-activated K+ conductance in THP-1 macrophages in a dose-dependent manner. In macrophages, ATP-induced K+ efflux plays a key role in activating the NLRP3 inflammasome. ATP-induced IL-1beta secretion was controlled by the KCa1.1 inhibitor iberiotoxin. NS1619 and NS309 (KCa1.1 and KCa3.1 activators respectively) induced the secretion of IL-1beta. This effect was inhibited by HCQ and also by iberiotoxin and clotrimazol (KCa3.1 inhibitor), arguing against off-target effect. In vitro, HCQ inhibited IL-1beta and caspase 1 activation induced by ATP in a dose-dependent manner. HCQ impaired K+ efflux induced by ATP. In vivo, HCQ inhibited caspase 1-dependent ATP-induced neutrophil recruitment. Our results show that HCQ inhibits Ca++-activated K+ channels. This effect may lead to impaired inflammasome activation. These results are the basis for i) a novel anti-inflammatory mechanism for HCQ and ii) a new strategy to target pro-rheumatic Ca++-activated K+ channels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Biomarkers
  • Caspase 1 / genetics
  • Caspase 1 / metabolism
  • Humans
  • Hydroxychloroquine / pharmacology*
  • Inflammasomes / metabolism*
  • Ion Channel Gating / drug effects*
  • Mice
  • Potassium Channels, Calcium-Activated / metabolism*

Substances

  • Biomarkers
  • Inflammasomes
  • Potassium Channels, Calcium-Activated
  • Hydroxychloroquine
  • Adenosine Triphosphate
  • Caspase 1