Resistance to Pseudomonas aeruginosa Chronic Lung Infection Requires Cystic Fibrosis Transmembrane Conductance Regulator-Modulated Interleukin-1 (IL-1) Release and Signaling through the IL-1 Receptor

Innate immunity is critical for clearingPseudomonas aeruginosa from the lungs. In response toP. aeruginosa infection, a central transcriptional regulator of innate immunity—NF-κB—is translocated within 15 min to the nuclei of respiratory epithelial cells expressing wild-type (WT) cystic fibrosis (CF) transmembrane conductance regulator (CFTR).P. aeruginosa clearance from lungs is impaired in CF, and rapid NF-κB nuclear translocation is defective in cells with mutant or missing CFTR. We used WT and mutantP. aeruginosa and strains of transgenic mice lacking molecules involved in innate immunity to identify additional mediators required forP. aeruginosa -induced rapid NF-κB nuclear translocation in lung epithelia. We found neither Toll-like receptor 2 (TLR2) nor TLR4 nor TLR5 were required for this response. However, both MyD88-deficient mice and interleukin-1 receptor (IL-1R)-deficient mice failed to rapidly translocate NF-κB to the nuclei of respiratory epithelial cells in response toP. aeruginosa . Cultured human bronchial epithelial cells rapidly released IL-1β in response toP. aeruginosa ; this process was maximized by expression of WT-CFTR and dramatically muted in cells with ΔF508-CFTR. The IL-1R antagonist blockedP. aeruginosa -induced NF-κB nuclear translocation. Oral inoculation via drinking water of IL-1R knockout mice resulted in higher rates of lung colonization and elevatedP. aeruginosa -specific antibody titers in a manner analogous to that of CFTR-deficient mice. Overall, rapid IL-1 release and signaling through IL-1R represent key steps in the innate immune response toP. aeruginosa infection, and this process is deficient in cells lacking functional CFTR.