期刊
IMMUNOLOGY AND CELL BIOLOGY
卷 100, 期 5, 页码 352-370出版社
WILEY
DOI: 10.1111/imcb.12547
关键词
Airway epithelium; cystic fibrosis; innate immunity; neutrophils; Pseudomonas; rhinovirus
资金
- NHMRC [1142505, 1141479]
- Telethon Kids Institute Plus 10 Award
- Cystic Fibrosis Foundation: Research Development Program [ROWE19R0]
- University of Western Australia
- Telethon Kids Institute
- National Health and Medical Research Council of Australia [1141479, 1142505] Funding Source: NHMRC
This study investigates the population of neutrophils in cystic fibrosis (CF) airways, which is associated with proteolytic lung damage. The study presents a laboratory model to understand the responses of airway epithelium and neutrophils following respiratory infection. The findings suggest that Pseudomonas aeruginosa is a trigger of acute airway inflammation and neutrophil primary granule exocytosis.
A population of neutrophils recruited into cystic fibrosis (CF) airways is associated with proteolytic lung damage, exhibiting high expression of primary granule exocytosis marker CD63 and reduced phagocytic receptor CD16. Causative factors for this population are unknown, limiting intervention. Here we present a laboratory model to characterize responses of differentiated airway epithelium and neutrophils following respiratory infection. Pediatric primary airway epithelial cells were cultured at the air-liquid interface, challenged individually or in combination with rhinovirus (RV) and Pseudomonas aeruginosa, then apically washed with medical saline to sample epithelial infection milieus. Cytokine multiplex analysis revealed epithelial antiviral signals, including IP-10 and RANTES, increased with exclusive RV infection but were diminished if P. aeruginosa was also present. Proinflammatory signals interleukin-1 alpha and beta were dominant in P. aeruginosa infection milieus. Infection washes were also applied to a published model of neutrophil transmigration into the airways. Neutrophils migrating into bacterial and viral-bacterial co-infection milieus exhibited the in vivo CF phenotype of increased CD63 expression and reduced CD16 expression, while neutrophils migrating into milieus of RV-infected or uninfected cultures did not. Individually, bacterial products lipopolysaccharide and N-formylmethionyl-leucyl-phenylalanine and isolated cytokine signals only partially activated this phenotype, suggesting that additional soluble factors in the infection microenvironment trigger primary granule release. Findings identify P. aeruginosa as a trigger of acute airway inflammation and neutrophil primary granule exocytosis, underscoring potential roles of airway microbes in prompting this neutrophil subset. Further studies are required to characterize microbes implicated in primary granule release, and identify potential therapeutic targets.
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