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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doaj-9f445eafc7404bd3ae406e739cc169ea2020-12-08T01:37:01ZengNature Publishing GroupScientific Reports2045-23222017-05-01711710.1038/s41598-017-01836-8Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquineMaría Eugenia Schroeder0Sofía Russo1Carlos Costa2Juliana Hori3Inés Tiscornia4Mariela Bollati-Fogolín5Darío S Zamboni6Gonzalo Ferreira7Ernesto Cairoli8Marcelo Hill9Laboratory of Immunoregulation and Inflammation, Institut Pasteur de MontevideoLaboratory of Immunoregulation and Inflammation, Institut Pasteur de MontevideoIon Channels Laboratory, Biophysics Department, Montevideo Faculty of Medicine, University of the RepublicDepartment of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo, FMRP/USPLaboratorio de Biotecnología, Facultad de Ingeniería-Universidad ORT UruguayLaboratorio de Biotecnología, Facultad de Ingeniería-Universidad ORT UruguayDepartment of Cell Biology, School of Medicine of Ribeirão Preto, University of São Paulo, FMRP/USPIon Channels Laboratory, Biophysics Department, Montevideo Faculty of Medicine, University of the RepublicUnit of Systemic Autoimmune Diseases, “C” Medical Clinic Prof. Dr. Juan Alonso Bao, Hospital of Clinics, Montevideo Faculty of Medicine, University of the RepublicLaboratory of Immunoregulation and Inflammation, Institut Pasteur de MontevideoAbstract 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.https://doi.org/10.1038/s41598-017-01836-8 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
María Eugenia Schroeder Sofía Russo Carlos Costa Juliana Hori Inés Tiscornia Mariela Bollati-Fogolín Darío S Zamboni Gonzalo Ferreira Ernesto Cairoli Marcelo Hill |
spellingShingle |
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 Scientific Reports |
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 Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-05-01 |
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. |
url |
https://doi.org/10.1038/s41598-017-01836-8 |
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