Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence

Eur Respir J. 2015 Sep;46(3):771-82. doi: 10.1183/09031936.00215114. Epub 2015 Aug 6.


Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infection-driven acute exacerbations. Despite the life-threatening nature of these exacerbations, the underlying mechanisms remain unclear, although a high number of neutrophils in the lungs of COPD patients is known to correlate with poor prognosis. Interleukin (IL)-22 is a cytokine that plays a pivotal role in lung antimicrobial defence and tissue protection. We hypothesised that neutrophils secrete proteases that may have adverse effects in COPD, by altering the IL-22 receptor (IL-22R)-dependent signalling.Using in vitro and in vivo approaches as well as reverse transcriptase quantitative PCR, flow cytometry and/or Western blotting techniques, we first showed that pathogens such as the influenza virus promote IL-22R expression in human bronchial epithelial cells, whereas Pseudomonas aeruginosa, bacterial lipopolysaccharide or cigarette smoke do not. Most importantly, neutrophil proteases cleave IL-22R and impair IL-22-dependent immune signalling and expression of antimicrobial effectors such as β-defensin-2. This proteolysis resulted in the release of a soluble fragment of IL-22R, which was detectable both in cellular and animal models as well as in sputa from COPD patients with acute exacerbations.Hence, our study reveals an unsuspected regulation by the proteolytic action of neutrophil enzymes of IL-22-dependent lung host response. This process probably enhances pathogen replication, and ultimately COPD exacerbations.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Blotting, Western
  • Cells, Cultured
  • Disease Models, Animal
  • Epithelial Cells / enzymology*
  • Epithelial Cells / microbiology
  • Humans
  • Immunity, Innate / drug effects*
  • Immunity, Innate / physiology
  • Mice
  • Neutrophils / drug effects
  • Neutrophils / metabolism*
  • Peptide Hydrolases / metabolism
  • Pseudomonas aeruginosa / drug effects
  • Pseudomonas aeruginosa / pathogenicity
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / immunology
  • Pulmonary Disease, Chronic Obstructive / microbiology*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Interleukin / immunology
  • Receptors, Interleukin / metabolism*
  • Sampling Studies
  • Sensitivity and Specificity
  • Smoking / adverse effects
  • Statistics, Nonparametric
  • beta-Defensins / pharmacology


  • Biomarkers
  • Receptors, Interleukin
  • beta-Defensins
  • interleukin-22 receptor
  • Peptide Hydrolases