期刊
CELLS
卷 11, 期 15, 页码 -出版社
MDPI
DOI: 10.3390/cells11152303
关键词
proteolysis; metalloproteinase; lung infection; junctional molecules; regeneration; exosomes
类别
资金
- German Research Foundation [DR1013/1-1]
- Ministry of Education and Research [BMBF16LW0140]
- HIPS-UdS TANDEM initiative (Saarland University)
Severe epithelial dysfunction is a major feature in the progress of bacterial pneumonia. The activation of ADAM17 plays a critical role in the infection of lung epithelial cells by Pseudomonas aeruginosa, and targeting ADAM17 may be a potential therapeutic option.
Severe epithelial dysfunction is one major hallmark throughout the pathophysiological progress of bacterial pneumonia. Junctional and cellular adhesion molecules (e.g., JAMA-A, ICAM-1), cytokines (e.g., TNF alpha), and growth factors (e.g., TGF alpha), controlling proper lung barrier function and leukocyte recruitment, are proteolytically cleaved and released into the extracellular space through a disintegrin and metalloproteinase (ADAM) 17. In cell-based assays, we could show that the protein expression, maturation, and activation of ADAM17 is upregulated upon infection of lung epithelial cells with Pseudomonas aeruginosa and Exotoxin A (ExoA), without any impact of infection by Streptococcus pneumoniae. The characterization of released extracellular vesicles/exosomes and the comparison to heat-inactivated bacteria revealed that this increase occurred in a cell-associated and toxin-dependent manner. Pharmacological targeting and gene silencing of ADAM17 showed that its activation during infection with Pseudomonas aeruginosa was critical for the cleavage of junctional adhesion molecule A (JAM-A) and epithelial cell survival, both modulating barrier integrity, epithelial regeneration, leukocyte adhesion and transepithelial migration. Thus, site-specific targeting of ADAM17 or blockage of the activating toxins may constitute a novel anti-infective therapeutic option in Pseudomonas aeruginosa lung infection preventing severe epithelial and organ dysfunctions and stimulating future translational studies.
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