Lasr-Deficient Pseudomonas Aeruginosa Variants Increase Airway Epithelial Micam-1 Expression And Enhance Neutrophilic Lung Inflammation

Author summaryCystic fibrosis (CF) patients develop progressive lung disease characterized by chronic airway infections, commonly caused by the opportunistic pathogen Pseudomonas aeruginosa, and excessive non-resolving neutrophilic inflammation. Loss of function mutations of the lasR quorum sensing transcription regulator gene commonly arise during chronic P. aeruginosa infections and are associated with increased lung inflammation. In this study, we demonstrated that loss-of-function lasR mutants induced increased mICAM-1 levels on airway epithelial cells compared to wild-type P. aeruginosa strains in cell culture and in murine infection models. This effect was caused by the loss of ICAM-1 degradation by LasR-regulated secreted protease, facilitated neutrophil adhesion, and was associated with increased neutrophilic lung inflammation. Our study provides novel insights into the P. aeruginosa-airway epithelial-neutrophil interactions, and demonstrates how a common pathoadaptation of P. aeruginosa may drive lung disease progression by exacerbating inflammation.Pseudomonas aeruginosa causes chronic airway infections, a major determinant of lung inflammation and damage in cystic fibrosis (CF). Loss-of-function lasR mutants commonly arise during chronic CF infections, are associated with accelerated lung function decline in CF patients and induce exaggerated neutrophilic inflammation in model systems. In this study, we investigated how lasR mutants modulate airway epithelial membrane bound ICAM-1 (mICAM-1), a surface adhesion molecule, and determined its impact on neutrophilic inflammation in vitro and in vivo. We demonstrated that LasR-deficient strains induce increased mICAM-1 levels in airway epithelial cells compared to wild-type strains, an effect attributable to the loss of mICAM-1 degradation by LasR-regulated proteases and associated with enhanced neutrophil adhesion. In a subacute airway infection model, we also observed that lasR mutant-infected mice displayed greater airway epithelial ICAM-1 expression and increased neutrophilic pulmonary inflammation. Our findings provide new insights into the intricate interplay between lasR mutants, LasR-regulated proteases and airway epithelial ICAM-1 expression, and reveal a new mechanism involved in the exaggerated inflammatory response induced by lasR mutants.