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

Hawez, Avin LU ; Al-Haidari, Amr LU ; Madhi, Raed LU ; Rahman, Milladur LU and Thorlacius, Henrik LU (2019) In Frontiers in Immunology 10.
Abstract

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.... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
histone, inflammation, microRNA, NETosis, neutrophils
in
Frontiers in Immunology
volume
10
article number
2462
publisher
Frontiers Media S. A.
external identifiers
  • pmid:31736940
  • scopus:85075114779
ISSN
1664-3224
DOI
10.3389/fimmu.2019.02462
language
English
LU publication?
yes
id
07b5b15c-912f-4aab-a4ef-cd3765d63ed7
date added to LUP
2019-12-02 14:26:01
date last changed
2019-12-03 03:00:03
@article{07b5b15c-912f-4aab-a4ef-cd3765d63ed7,
  abstract     = {<p>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.</p>},
  author       = {Hawez, Avin and Al-Haidari, Amr and Madhi, Raed and Rahman, Milladur and Thorlacius, Henrik},
  issn         = {1664-3224},
  language     = {eng},
  publisher    = {Frontiers Media S. A.},
  series       = {Frontiers in Immunology},
  title        = {MiR-155 Regulates PAD4-Dependent Formation of Neutrophil Extracellular Traps},
  url          = {http://dx.doi.org/10.3389/fimmu.2019.02462},
  doi          = {10.3389/fimmu.2019.02462},
  volume       = {10},
  year         = {2019},
}