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MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps

Accumulating data suggest that neutrophil extracellular traps (NETs) exert a key function in several diseases. Peptidylarginine deiminase 4 (PAD4) regulates NET formation via citrullination of histones. The aim of this study was to examine the role of miR-155 in controlling PAD4-dependent generation...

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Autores principales: Hawez, Avin, Al-Haidari, Amr, Madhi, Raed, Rahman, Milladur, Thorlacius, Henrik
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838784/
https://www.ncbi.nlm.nih.gov/pubmed/31736940
http://dx.doi.org/10.3389/fimmu.2019.02462
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author Hawez, Avin
Al-Haidari, Amr
Madhi, Raed
Rahman, Milladur
Thorlacius, Henrik
author_facet Hawez, Avin
Al-Haidari, Amr
Madhi, Raed
Rahman, Milladur
Thorlacius, Henrik
author_sort Hawez, Avin
collection PubMed
description Accumulating data suggest that neutrophil extracellular traps (NETs) exert a key function in several diseases. Peptidylarginine deiminase 4 (PAD4) regulates NET formation via citrullination of histones. The aim of this study was to examine the role of miR-155 in controlling PAD4-dependent generation of NETs. Bone marrow neutrophils were stimulated with PMA and MIP-2. Pre-incubation of neutrophils with translational inhibitors (cycloheximide or puromycin) markedly decreased NET formation induced by PMA or MIP-2. Neutrophil transfection with a mimic miR-155 increased PMA-induced PAD4 mRNA expression and NET formation. In contrast, transfection with an antagomiR-155 decreased induction of PAD4 mRNA and NETs in response to PMA challenge. Bioinformatical examination of PAD4 revealed a potential binding site in AU-rich elements at the 3′-UTR region. MiR-155 binding to PAD4 was examined by use of target site blockers and RNA immunoprecipitation, revealing that miR-155 regulation of PAD4 mRNA is mediated via AU-rich elements in the 3′-UTR region. In conclusion, our findings demonstrate that miR-155 positively regulates neutrophil expression of PAD4 and expulsion of extracellular traps. Thus, our novel results indicate that targeting miR-155 might be useful to inhibit exaggerated NET generation in inflammatory diseases.
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spelling pubmed-68387842019-11-15 MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps Hawez, Avin Al-Haidari, Amr Madhi, Raed Rahman, Milladur Thorlacius, Henrik Front Immunol Immunology Accumulating data suggest that neutrophil extracellular traps (NETs) exert a key function in several diseases. Peptidylarginine deiminase 4 (PAD4) regulates NET formation via citrullination of histones. The aim of this study was to examine the role of miR-155 in controlling PAD4-dependent generation of NETs. Bone marrow neutrophils were stimulated with PMA and MIP-2. Pre-incubation of neutrophils with translational inhibitors (cycloheximide or puromycin) markedly decreased NET formation induced by PMA or MIP-2. Neutrophil transfection with a mimic miR-155 increased PMA-induced PAD4 mRNA expression and NET formation. In contrast, transfection with an antagomiR-155 decreased induction of PAD4 mRNA and NETs in response to PMA challenge. Bioinformatical examination of PAD4 revealed a potential binding site in AU-rich elements at the 3′-UTR region. MiR-155 binding to PAD4 was examined by use of target site blockers and RNA immunoprecipitation, revealing that miR-155 regulation of PAD4 mRNA is mediated via AU-rich elements in the 3′-UTR region. In conclusion, our findings demonstrate that miR-155 positively regulates neutrophil expression of PAD4 and expulsion of extracellular traps. Thus, our novel results indicate that targeting miR-155 might be useful to inhibit exaggerated NET generation in inflammatory diseases. Frontiers Media S.A. 2019-11-01 /pmc/articles/PMC6838784/ /pubmed/31736940 http://dx.doi.org/10.3389/fimmu.2019.02462 Text en Copyright © 2019 Hawez, Al-Haidari, Madhi, Rahman and Thorlacius. 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) and the copyright owner(s) 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
Hawez, Avin
Al-Haidari, Amr
Madhi, Raed
Rahman, Milladur
Thorlacius, Henrik
MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
title MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
title_full MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
title_fullStr MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
title_full_unstemmed MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
title_short MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps
title_sort mir-155 regulates pad4-dependent formation of neutrophil extracellular traps
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838784/
https://www.ncbi.nlm.nih.gov/pubmed/31736940
http://dx.doi.org/10.3389/fimmu.2019.02462
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