A Novel Biological Role for Peptidyl-Arginine Deiminases: Citrullination of Cathelicidin LL-37 Controls the Immunostimulatory Potential of Cell-Free DNA

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • Alicia Wong, Jagiellonian University
  • ,
  • Danuta Bryzek, Jagiellonian University
  • ,
  • Ewelina Dobosz, Jagiellonian University
  • ,
  • Carsten Scavenius
  • Pavel Svoboda, Centers for Disease Control and Prevention, Atlanta
  • ,
  • Maria Rapala-Kozik, Jagiellonian University
  • ,
  • Adam Lesner, University of Gdánsk
  • ,
  • Ivo Frydrych, Palacký University
  • ,
  • Jan Enghild
  • Piotr Mydel, Jagiellonian University, University of Bergen
  • ,
  • Jan Pohl, Centers for Disease Control and Prevention, Atlanta
  • ,
  • Paul R Thompson, UMass Medical School
  • ,
  • Jan Potempa, Jagiellonian University, University of Louisville
  • ,
  • Joanna Koziel, Jagiellonian University

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.

Original languageEnglish
JournalJournal of Immunology
Volume200
Issue7
Pages (from-to)2327-2340
ISSN0022-1767
DOIs
Publication statusPublished - 1 Apr 2018

    Research areas

  • Journal Article

See relations at Aarhus University Citationformats

ID: 121935247