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

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 be...

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Autores principales:	María Eugenia Schroeder, Sofía Russo, Carlos Costa, Juliana Hori, Inés Tiscornia, Mariela Bollati-Fogolín, Darío S Zamboni, Gonzalo Ferreira, Ernesto Cairoli, Marcelo Hill
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9f445eafc7404bd3ae406e739cc169ea
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spelling	oai:doaj.org-article:9f445eafc7404bd3ae406e739cc169ea2021-12-02T15:06:22ZPro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine10.1038/s41598-017-01836-82045-2322https://doaj.org/article/9f445eafc7404bd3ae406e739cc169ea2017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01836-8https://doaj.org/toc/2045-2322Abstract 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.María Eugenia SchroederSofía RussoCarlos CostaJuliana HoriInés TiscorniaMariela Bollati-FogolínDarío S ZamboniGonzalo FerreiraErnesto CairoliMarcelo HillNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-7 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q María Eugenia Schroeder Sofía Russo Carlos Costa Juliana Hori Inés Tiscornia Mariela Bollati-Fogolín Darío S Zamboni Gonzalo Ferreira Ernesto Cairoli Marcelo Hill Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine
description	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.
format	article
author	María Eugenia Schroeder Sofía Russo Carlos Costa Juliana Hori Inés Tiscornia Mariela Bollati-Fogolín Darío S Zamboni Gonzalo Ferreira Ernesto Cairoli Marcelo Hill
author_facet	María Eugenia Schroeder Sofía Russo Carlos Costa Juliana Hori Inés Tiscornia Mariela Bollati-Fogolín Darío S Zamboni Gonzalo Ferreira Ernesto Cairoli Marcelo Hill
author_sort	María Eugenia Schroeder
title	Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine
title_short	Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine
title_full	Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine
title_fullStr	Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine
title_full_unstemmed	Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine
title_sort	pro-inflammatory ca++-activated k+ channels are inhibited by hydroxychloroquine
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/9f445eafc7404bd3ae406e739cc169ea
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Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine

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