Format

Send to

Choose Destination
J Immunol. 2018 Apr 1;200(7):2327-2340. doi: 10.4049/jimmunol.1701391. Epub 2018 Feb 23.

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

Author information

1
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Krakow, Poland.
2
Interdisciplinary Nanoscience Center, Aarhus University, 8000 Aarhus, Denmark.
3
Department of Molecular Biology and Genetics, Aarhus University, 8000 Aarhus, Denmark.
4
Division of Scientific Resources, Centers for Disease Control and Prevention, Atlanta, GA 30329.
5
Department of Comparative Biochemistry and Bioanalytics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Krakow, Poland.
6
Faculty of Chemistry, University of Gdansk, 80-309 Gdansk, Poland.
7
Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, 77126 Olomouc, Czech Republic.
8
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway.
9
Department of Biochemistry and Molecular Pharmacology, UMass Medical School, Worcester, MA 01605; and.
10
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, 30-387 Krakow, Poland; joanna.koziel@uj.edu.pl jan.potempa@louisville.edu.
11
Center for Oral Health and Systemic Disease, University of Louisville School of Dentistry, University of Louisville, Louisville, KY 40202.

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.

PMID:
29475987
PMCID:
PMC5860981
[Available on 2019-04-01]
DOI:
10.4049/jimmunol.1701391

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center