Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis
Anaphylaxis, the most serious and life-threatening allergic reaction, produces the release of inflammatory mediators by mast cells and basophils. Regulator of calcineurin 1 (Rcan1) is a negative regulator of mast-cell degranulation. The action of mediators leads to vasodilation and an increase in va...
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Frontiers Media S.A.
2017-10-01
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Series: | Frontiers in Immunology |
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Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2017.01323/full |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Constanza Ballesteros-Martinez Nerea Mendez-Barbero Alma Montalvo-Yuste Bettina M. Jensen Aída Gomez-Cardenosa Lotte Klitfod María Garrido-Arandia Gloria Alvarez-Llamas Carlos Pastor-Vargas Fernando Vivanco Lene Heise Garvey Javier Cuesta-Herranz Javier Cuesta-Herranz Lars K. Poulsen Vanesa Esteban Vanesa Esteban |
spellingShingle |
Constanza Ballesteros-Martinez Nerea Mendez-Barbero Alma Montalvo-Yuste Bettina M. Jensen Aída Gomez-Cardenosa Lotte Klitfod María Garrido-Arandia Gloria Alvarez-Llamas Carlos Pastor-Vargas Fernando Vivanco Lene Heise Garvey Javier Cuesta-Herranz Javier Cuesta-Herranz Lars K. Poulsen Vanesa Esteban Vanesa Esteban Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis Frontiers in Immunology anaphylaxis endothelial cells vascular permeability regulator of calcineurin 1 histamine |
author_facet |
Constanza Ballesteros-Martinez Nerea Mendez-Barbero Alma Montalvo-Yuste Bettina M. Jensen Aída Gomez-Cardenosa Lotte Klitfod María Garrido-Arandia Gloria Alvarez-Llamas Carlos Pastor-Vargas Fernando Vivanco Lene Heise Garvey Javier Cuesta-Herranz Javier Cuesta-Herranz Lars K. Poulsen Vanesa Esteban Vanesa Esteban |
author_sort |
Constanza Ballesteros-Martinez |
title |
Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis |
title_short |
Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis |
title_full |
Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis |
title_fullStr |
Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis |
title_full_unstemmed |
Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in Anaphylaxis |
title_sort |
endothelial regulator of calcineurin 1 promotes barrier integrity and modulates histamine-induced barrier dysfunction in anaphylaxis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2017-10-01 |
description |
Anaphylaxis, the most serious and life-threatening allergic reaction, produces the release of inflammatory mediators by mast cells and basophils. Regulator of calcineurin 1 (Rcan1) is a negative regulator of mast-cell degranulation. The action of mediators leads to vasodilation and an increase in vascular permeability, causing great loss of intravascular volume in a short time. Nevertheless, the molecular basis remains unexplored on the vascular level. We investigated Rcan1 expression induced by histamine, platelet-activating factor (PAF), and epinephrine in primary human vein (HV)-/artery (HA)-derived endothelial cells (ECs) and human dermal microvascular ECs (HMVEC-D). Vascular permeability was analyzed in vitro in human ECs with forced Rcan1 expression using Transwell migration assays and in vivo using Rcan1 knockout mice. Histamine, but neither PAF nor epinephrine, induced Rcan1-4 mRNA and protein expression in primary HV-ECs, HA-ECs, and HMVEC-D through histamine receptor 1 (H1R). These effects were prevented by pharmacological inhibition of calcineurin with cyclosporine A. Moreover, intravenous histamine administration increased Rcan1 expression in lung tissues of mice undergoing experimental anaphylaxis. Functional in vitro assays showed that overexpression of Rcan1 promotes barrier integrity, suggesting a role played by this molecule in vascular permeability. Consistent with these findings, in vivo models of subcutaneous and intravenous histamine-mediated fluid extravasation showed increased response in skin, aorta, and lungs of Rcan1-deficient mice compared with wild-type animals. These findings reveal that endothelial Rcan1 is synthesized in response to histamine through a calcineurin-sensitive pathway and may reduce barrier breakdown, thus contributing to the strengthening of the endothelium and resistance to anaphylaxis. These new insights underscore its potential role as a regulator of sensitivity to anaphylaxis in humans. |
topic |
anaphylaxis endothelial cells vascular permeability regulator of calcineurin 1 histamine |
url |
http://journal.frontiersin.org/article/10.3389/fimmu.2017.01323/full |
work_keys_str_mv |
AT constanzaballesterosmartinez endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT nereamendezbarbero endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT almamontalvoyuste endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT bettinamjensen endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT aidagomezcardenosa endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT lotteklitfod endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT mariagarridoarandia endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT gloriaalvarezllamas endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT carlospastorvargas endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT fernandovivanco endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT leneheisegarvey endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT javiercuestaherranz endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT javiercuestaherranz endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT larskpoulsen endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT vanesaesteban endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis AT vanesaesteban endothelialregulatorofcalcineurin1promotesbarrierintegrityandmodulateshistamineinducedbarrierdysfunctioninanaphylaxis |
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doaj-10976b7a6f2144a18ac2d99c75f36d862020-11-24T21:09:02ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-10-01810.3389/fimmu.2017.01323275707Endothelial Regulator of Calcineurin 1 Promotes Barrier Integrity and Modulates Histamine-Induced Barrier Dysfunction in AnaphylaxisConstanza Ballesteros-Martinez0Nerea Mendez-Barbero1Alma Montalvo-Yuste2Bettina M. Jensen3Aída Gomez-Cardenosa4Lotte Klitfod5María Garrido-Arandia6Gloria Alvarez-Llamas7Carlos Pastor-Vargas8Fernando Vivanco9Lene Heise Garvey10Javier Cuesta-Herranz11Javier Cuesta-Herranz12Lars K. Poulsen13Vanesa Esteban14Vanesa Esteban15Department of Immunology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainDepartment of Vascular Physiopathology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainDepartment of Immunology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainAllergy Clinic, Gentofte Hospital, Copenhagen University Hospital, Hellerup, DenmarkDepartment of Allergy, Fundación Jiménez Díaz, Madrid, SpainSurgery Department, Gentofte Hospital, Copenhagen University Hospital, Hellerup, DenmarkCenter for Plant Biotechnology and Genomics, Technical University of Madrid, Madrid, SpainDepartment of Immunology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainDepartment of Immunology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainDepartment of Immunology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainAllergy Clinic, Gentofte Hospital, Copenhagen University Hospital, Hellerup, DenmarkDepartment of Immunology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainDepartment of Allergy, Fundación Jiménez Díaz, Madrid, SpainAllergy Clinic, Gentofte Hospital, Copenhagen University Hospital, Hellerup, DenmarkDepartment of Immunology, IIS-Fundación Jiménez Díaz, Autonomous University of Madrid, Madrid, SpainAllergy Clinic, Gentofte Hospital, Copenhagen University Hospital, Hellerup, DenmarkAnaphylaxis, the most serious and life-threatening allergic reaction, produces the release of inflammatory mediators by mast cells and basophils. Regulator of calcineurin 1 (Rcan1) is a negative regulator of mast-cell degranulation. The action of mediators leads to vasodilation and an increase in vascular permeability, causing great loss of intravascular volume in a short time. Nevertheless, the molecular basis remains unexplored on the vascular level. We investigated Rcan1 expression induced by histamine, platelet-activating factor (PAF), and epinephrine in primary human vein (HV)-/artery (HA)-derived endothelial cells (ECs) and human dermal microvascular ECs (HMVEC-D). Vascular permeability was analyzed in vitro in human ECs with forced Rcan1 expression using Transwell migration assays and in vivo using Rcan1 knockout mice. Histamine, but neither PAF nor epinephrine, induced Rcan1-4 mRNA and protein expression in primary HV-ECs, HA-ECs, and HMVEC-D through histamine receptor 1 (H1R). These effects were prevented by pharmacological inhibition of calcineurin with cyclosporine A. Moreover, intravenous histamine administration increased Rcan1 expression in lung tissues of mice undergoing experimental anaphylaxis. Functional in vitro assays showed that overexpression of Rcan1 promotes barrier integrity, suggesting a role played by this molecule in vascular permeability. Consistent with these findings, in vivo models of subcutaneous and intravenous histamine-mediated fluid extravasation showed increased response in skin, aorta, and lungs of Rcan1-deficient mice compared with wild-type animals. These findings reveal that endothelial Rcan1 is synthesized in response to histamine through a calcineurin-sensitive pathway and may reduce barrier breakdown, thus contributing to the strengthening of the endothelium and resistance to anaphylaxis. These new insights underscore its potential role as a regulator of sensitivity to anaphylaxis in humans.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01323/fullanaphylaxisendothelial cellsvascular permeabilityregulator of calcineurin 1histamine |