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Front. Immunol. | doi: 10.3389/fimmu.2019.02462

MiR-155 regulates PAD4-dependent formation of neutrophil extracellular traps

  • 1Department of Clinical Sciences, Faculty of Medicine, Lund University, Sweden

Accumulating data suggest that neutrophil extracellular traps (NETs) play a key role 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. Bioinformatics analysis predicted a putative binding site in AU-rich elements at the 3´-UTR of PAD4. MiR-155 binding to PAD4 was verified using target site blockers and functionally validated using RNA immunoprecipitation assays, showing that miR-155-dependent regulation of PAD4 mRNA is mediated by AU-rich elements present in the 3´-UTR region. In conclusion, our results demonstrate that miR-155 positively regulates neutrophil expression of PAD4 and expulsion of extracellular traps. Thus, our novel findings suggest that miR-155 could be used to inhibit exaggerated NET generation in inflammatory diseases.

Keywords: microRNA, histone, Inflammation, Neutrophil, NETosis.

Received: 02 Jul 2019; Accepted: 02 Oct 2019.

Copyright: © 2019 Hawez, al-haidari, Madhi, Rahman and Thorlacius. 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.

* Correspondence: Prof. Henrik Thorlacius, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, 202 13, Sweden, henrik.thorlacius@med.lu.se