A novel biological role for peptidyl-arginine deiminases: citrullination of cathelicidin LL-37 controls the immunostimulatory potential of cell-free DNA

Alicia Wong , Danuta Bryzek , Ewelina Dobosz , Carsten Scavenius , Pavel Svoboda , Maria Rapala-Kozik , Adam Lesner , Ivo Frydrych , Jan Enghild , Piotr Mydel , Jan Pohl , Paul R. Thompson , Jan Potempa , Joanna Koziel

Abstract

LL-37, the only human cathelicidin that is released during inflammation, is a potent regulator of immune responses by facilitating delivery of oligonucleotides to intracellular TLR-9, thereby enhancing the response of human plasmacytoid dendritic cells (pDCs) to extracellular DNA. Although important for pathogen recognition, this mechanism may facilitate development of autoimmune diseases. In this article, we show that citrullination of LL-37 by peptidyl-arginine deiminases (PADs) hindered peptide-dependent DNA uptake and sensing by pDCs. In contrast, carbamylation of the peptide (homocitrullination of Lys residues) had no effect. The efficiency of LL-37 binding to oligonucleotides and activation of pDCs was found to be inversely proportional to the number of citrullinated residues in the peptide. Similarly, preincubation of carbamylated LL-37 with PAD2 abrogated the peptide’s ability to bind DNA. Conversely, LL-37 with Arg residues substituted by homoarginine, which cannot be deiminated, elicited full activity of native LL-37 regardless of PAD2 treatment. Taken together, the data showed that citrullination abolished LL-37 ability to bind DNA and altered the immunomodulatory function of the peptide. Both activities were dependent on the proper distribution of guanidinium side chains in the native peptide sequence. Moreover, our data suggest that cathelicidin/LL-37 is citrullinated by PADs during NET formation, thus affecting the inflammatory potential of NETs. Together this may represent a novel mechanism for preventing the breakdown of immunotolerance, which is dependent on the response of APCs to self-molecules (including cell-free DNA); overactivation may facilitate development of autoimmunity.
Author Alicia Wong
Alicia Wong,,
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, Danuta Bryzek
Danuta Bryzek,,
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, Ewelina Dobosz
Ewelina Dobosz,,
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, Carsten Scavenius
Carsten Scavenius,,
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, Pavel Svoboda
Pavel Svoboda,,
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, Maria Rapala-Kozik
Maria Rapala-Kozik,,
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, Adam Lesner PAB
Adam Lesner,,
- Laboratory of Biochemical Analytics
, Ivo Frydrych
Ivo Frydrych,,
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, Jan Enghild
Jan Enghild,,
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, Piotr Mydel
Piotr Mydel,,
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et al.`
Journal seriesJournal of Immunology, ISSN 0022-1767
Issue year2018
Vol200
No7
Pages2327-2340
Publication size in sheets0.65
DOIDOI:10.4049/jimmunol.1701391
Languageen angielski
Score (nominal)35
ScoreMinisterial score = 35.0, 19-06-2018, ArticleFromJournal
Ministerial score (2013-2016) = 35.0, 19-06-2018, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 4.856 (2) - 2016=5.185 (5)
Citation count*1 (2018-09-20)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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