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., TNFα), and growth factors (e.g., TGFα), 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
