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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02481

Citrullination licenses calpain to decondense nuclei in neutrophil extracellular trap formation

  • 1University Hospital Erlangen, Germany
  • 2Ghent University, Belgium
  • 3Vita-Salute San Raffaele University, Italy
  • 4Queen's University, Canada
  • 5University of Giessen, Germany

Neutrophils respond to various stimuli by decondensing and releasing nuclear chromatin characterized by citrullinated histones as neutrophil extracellular traps (NETs). This achieves pathogen immobilisation or initiation of thrombosis, yet the molecular mechanisms of NET formation remain elusive. Peptidyl arginine deiminase-4 (PAD4) achieves protein citrullination and has been intricately linked to NET formation. Here we show that citrullination represents a major regulator of proteolysis in the course of NET formation. Elevated cytosolic calcium levels trigger both peptidylarginine deiminase-4 (PAD4) and calpain activity in neutrophils resulting in nuclear decondensation typical of NETs. Interestingly, PAD4 relies on proteolysis by calpain to achieve efficient nuclear lamina breakdown and chromatin decondensation. Pharmacological or genetic inhibition of PAD4 and calpain strongly inhibit chromatin decondensation of human and murine neutrophils in response to calcium ionophores as well as the proteolysis of nuclear proteins like lamin B1 and high mobility group box protein 1 (HMGB1). Taken together, the concerted action of PAD4 and calpain induces nuclear decondensation in the course of calcium-mediated NET formation.

Keywords: Neutrophil (PMN), citrullination/deimination, PAD4., Calpain, Cell Death, Extracellular traps (ETs), Proteolysis, Posttranslation modifications, Chromatin

Received: 16 Jul 2019; Accepted: 04 Oct 2019.

Copyright: © 2019 Gößwein, Lindemann, Mahajan, Maueroeder, Martini, Patankar, Schett, Becker, Wirtz, Naumann-Bartsch, Bianchi, Greer, Lochnit, Herrmann, Neurath and Leppkes. 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: Dr. Moritz Leppkes, University Hospital Erlangen, Erlangen, 91054, Bavaria, Germany, Moritz.Leppkes@uk-erlangen.de