Neutrophil-derived peptidyl arginine deiminase activity contributes to pulmonary emphysema by enhancing elastin degradation

Mark P. Murphy, David Hunt, Malcolm Herron, Jake McDonnell, Rashed Alshuhoumi, Lorcan P. McGarvey, Aurelie Fabre, Helen O'Brien, Cormac McCarthy, S. Lorraine Martin, Noel G. McElvaney, Emer P. Reeves*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

In chronic obstructive pulmonary disease (COPD), inflammation gives rise to protease-mediated degradation of the key extracellular matrix protein, elastin, which causes irreversible loss of pulmonary function. Intervention against proteolysis has met with limited success in COPD, due in part to our incomplete understanding of the mechanisms that underlie disease pathogenesis. Peptidyl arginine deiminase (PAD) enzymes are a known modifier of proteolytic susceptibility, but their involvement in COPD in the lungs of affected individuals is underexplored. In this study, we showed that enzyme isotypes PAD2 and PAD4 are present in primary granules of neutrophils and that cells from people with COPD release increased levels of PADs when compared with neutrophils of healthy control subjects. By examining bronchoalveolar lavage and lung tissue samples of patients with COPD or matched smoking and nonsmoking counterparts with normal lung function, we reveal that COPD presents with markedly increased airway concentrations of PADs. Ex vivo, we established citrullinated elastin in the peripheral airways of people with COPD, and in vitro, elastin citrullination significantly enhanced its proteolytic degradation by serine and matrix metalloproteinases, including neutrophil elastase and matrix metalloprotease-12, respectively. These results provide a mechanism by which neutrophil-released PADs affect lung function decline, indicating promise for the future development of PAD-based
therapeutics for preserving lung function in patients with COPD.
Original languageEnglish
Number of pages11
JournalJournal of Immunology
Volume213
Early online date17 May 2024
DOIs
Publication statusEarly online date - 17 May 2024

Keywords

  • COPD
  • neutrophils
  • peptide arginine deiminase
  • elastin
  • neutrophil elastase
  • matrix metalloproteases

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