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

Abstract

Chronic obstructive pulmonary disease (COPD) is punctuated by episodes of infectiondriven 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. @ERSpublications Neutrophil proteases alter lung antimicrobial defence and may predispose to infection-triggered COPD exacerbations http://ow.ly/MHqEt

Advanced Role of Neutrophils in Common Respiratory Diseases

“…[94]. Although neutrophils in COPD patients' airway mucosa play a key role in antimicrobial defense theoretically as described in present review, a high number of neutrophils in patients' lungs are believed to correlate with poor prognosis [95]. It is well known to us all that neutrophil is an important part in maintaining our host defense and responding to injury and microbial infection.…”

“…Neutrophil-derived proteases may contribute to COPD by impairing the antimicrobial IL-22/IL-22R signaling pathway and decreasing the expression of antimicrobial effectors such as β -defensin-2. This process probably enhances pathogen replication and ultimately causes COPD exacerbations [95]. …”

Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection

“…This is during the same time that the IL-22Ra1 is increased on epithelial cells. 5,28 These changes allow the lung to become a more permissive environment for IL-22 activity. This has been confirmed by microarray studies in which only 431 genes were differentially regulated after IL-22 treatment in naive mice as opposed to 1231 genes after IL-22 treatment in influenza-infected mice.…”

New therapies for the prevention and treatment of exacerbations of bronchiectasis

“…Notably, macrolides inhibit P. aeruginosa virulence factors and may also have some antimicrobial effect and so combined treatment may be beneficial in patients with P. aeruginosa infection. (55,56) Similarly, patients who continue to exacerbate despite macrolide therapy may benefit from an alternative oral antibiotic or a trial of an inhaled antibiotic.…”