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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-12

AUTHORS

María Eugenia Schroeder, Sofía Russo, Carlos Costa, Juliana Hori, Inés Tiscornia, Mariela Bollati-Fogolín, Darío S Zamboni, Gonzalo Ferreira, Ernesto Cairoli, Marcelo Hill

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. More... »

PAGES

1892

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-017-01836-8

DOI

http://dx.doi.org/10.1038/s41598-017-01836-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1085378964

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28507328


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32 schema:description 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<sup>++</sup>-activated K<sup>+</sup> conductance in THP-1 macrophages in a dose-dependent manner. In macrophages, ATP-induced K<sup>+</sup> 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<sup>+</sup> efflux induced by ATP. In vivo, HCQ inhibited caspase 1-dependent ATP-induced neutrophil recruitment. Our results show that HCQ inhibits Ca<sup>++</sup>-activated K<sup>+</sup> 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<sup>++</sup>-activated K<sup>+</sup> channels.
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