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P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production

Tumor necrosis factor (TNF)-α is a major pro-inflammatory cytokine produced in response to toll-like receptor stimulation. TNF-α release is controlled by the activity of TNF-α converting enzyme (TACE) that cut membrane-bound TNF-α to shed its ectodomain as a soluble cytokine. The purinergic receptor...

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Autores principales: Barberà-Cremades, Maria, Gómez, Ana I., Baroja-Mazo, Alberto, Martínez-Alarcón, Laura, Martínez, Carlos M., de Torre-Minguela, Carlos, Pelegrín, Pablo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523084/
https://www.ncbi.nlm.nih.gov/pubmed/28791020
http://dx.doi.org/10.3389/fimmu.2017.00862
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author Barberà-Cremades, Maria
Gómez, Ana I.
Baroja-Mazo, Alberto
Martínez-Alarcón, Laura
Martínez, Carlos M.
de Torre-Minguela, Carlos
Pelegrín, Pablo
author_facet Barberà-Cremades, Maria
Gómez, Ana I.
Baroja-Mazo, Alberto
Martínez-Alarcón, Laura
Martínez, Carlos M.
de Torre-Minguela, Carlos
Pelegrín, Pablo
author_sort Barberà-Cremades, Maria
collection PubMed
description Tumor necrosis factor (TNF)-α is a major pro-inflammatory cytokine produced in response to toll-like receptor stimulation. TNF-α release is controlled by the activity of TNF-α converting enzyme (TACE) that cut membrane-bound TNF-α to shed its ectodomain as a soluble cytokine. The purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is activated in response to elevated concentrations of extracellular ATP and induces different pro-inflammatory pathways in macrophages to establish an inflammatory response. P2X7 receptor promotes the activation of the inflammasome and the release of interleukin-1β, the production of inflammatory lipids, and the generation of reactive oxygen species. In this study, we analyzed the mechanism of P2X7 receptor responsible of TNF-α release after priming macrophages with LPS doses ≤100 ng/ml. We found that P2X7 receptor increases the extracellular activity of TACE through the release of the mature form of TACE in exosomes. This effect was blocked using P2X7 receptor inhibitors or in macrophages obtained from P2X7 receptor-deficient mice. Elevation of intracellular Ca(2+) and p38 mitogen-activated protein kinase after P2X7 receptor activation were involved in the release of TACE, which was able to process TNF-α on nearby expressing cells. Finally, we observed an increase of TNF-α in the peritoneal lavage of mice treated with LPS and ATP. In conclusion, P2X7 receptor induces the release of TACE in exosomes to the extracellular compartment that could amplify the pro-inflammatory signal associated to this receptor. These results are important for the development of therapeutics targeting P2X7 receptor.
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spelling pubmed-55230842017-08-08 P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production Barberà-Cremades, Maria Gómez, Ana I. Baroja-Mazo, Alberto Martínez-Alarcón, Laura Martínez, Carlos M. de Torre-Minguela, Carlos Pelegrín, Pablo Front Immunol Immunology Tumor necrosis factor (TNF)-α is a major pro-inflammatory cytokine produced in response to toll-like receptor stimulation. TNF-α release is controlled by the activity of TNF-α converting enzyme (TACE) that cut membrane-bound TNF-α to shed its ectodomain as a soluble cytokine. The purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is activated in response to elevated concentrations of extracellular ATP and induces different pro-inflammatory pathways in macrophages to establish an inflammatory response. P2X7 receptor promotes the activation of the inflammasome and the release of interleukin-1β, the production of inflammatory lipids, and the generation of reactive oxygen species. In this study, we analyzed the mechanism of P2X7 receptor responsible of TNF-α release after priming macrophages with LPS doses ≤100 ng/ml. We found that P2X7 receptor increases the extracellular activity of TACE through the release of the mature form of TACE in exosomes. This effect was blocked using P2X7 receptor inhibitors or in macrophages obtained from P2X7 receptor-deficient mice. Elevation of intracellular Ca(2+) and p38 mitogen-activated protein kinase after P2X7 receptor activation were involved in the release of TACE, which was able to process TNF-α on nearby expressing cells. Finally, we observed an increase of TNF-α in the peritoneal lavage of mice treated with LPS and ATP. In conclusion, P2X7 receptor induces the release of TACE in exosomes to the extracellular compartment that could amplify the pro-inflammatory signal associated to this receptor. These results are important for the development of therapeutics targeting P2X7 receptor. Frontiers Media S.A. 2017-07-24 /pmc/articles/PMC5523084/ /pubmed/28791020 http://dx.doi.org/10.3389/fimmu.2017.00862 Text en Copyright © 2017 Barberà-Cremades, Gómez, Baroja-Mazo, Martínez-Alarcón, Martínez, de Torre-Minguela and Pelegrín. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Barberà-Cremades, Maria
Gómez, Ana I.
Baroja-Mazo, Alberto
Martínez-Alarcón, Laura
Martínez, Carlos M.
de Torre-Minguela, Carlos
Pelegrín, Pablo
P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production
title P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production
title_full P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production
title_fullStr P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production
title_full_unstemmed P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production
title_short P2X7 Receptor Induces Tumor Necrosis Factor-α Converting Enzyme Activation and Release to Boost TNF-α Production
title_sort p2x7 receptor induces tumor necrosis factor-α converting enzyme activation and release to boost tnf-α production
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523084/
https://www.ncbi.nlm.nih.gov/pubmed/28791020
http://dx.doi.org/10.3389/fimmu.2017.00862
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