Abstract
Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1β in lung pathology using the experimental F508del-CFTR murine model on C57BL/6 genetic background (Cftr tm1eur or d/d), on double deficient for d/d and type 1 interleukin-1 receptor (d/d X IL-1R1−/−), and antibody neutralization. At steady state, young adult d/d mice did not show any signs of spontaneous lung inflammation. However, IL-1R1 deficiency conferred partial protection to repeated P. aeruginosa endotoxins/LPS lung instillation in d/d mice, as 50% of d/d mice succumbed to inflammation, whereas all d/d x IL-1R1−/− double mutants survived with lower initial weight loss and less pulmonary collagen and mucus production, suggesting that the absence of IL-1R1 signaling is protective in d/d mice in LPS-induced lung damage. Using P. aeruginosa acute lung infection we found heightened neutrophil recruitment in d/d mice with higher epithelial damage, increased bacterial load in BALF, and augmented IL-1β and TNF-α in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1β signaling in response to P. aeruginosa. IL-1β antibody neutralization had no effect on lung homeostasis in either d/d or WT mice, however P. aeruginosa induced lung inflammation and bacterial load were diminished by IL-1β antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1β production and reduced bacterial clearance. Further, we show that neutralization of IL-1β in d/d mice through the double mutation d/d x IL-1R1−/− and in WT via antibody neutralization attenuates inflammation. This supports the notion that intervention in the IL-1R1/IL-1β pathway may be detrimental in CF patients.
Highlights
Cystic fibrosis (CF) is an autosomal recessive genetic disease that affects 1 newborn out of 3,500 in the USA (WHO), and 1 per 2,000–3,000 in Europe, with an average 40-year life expectancy
Since LPS, P. aeruginosa [14,15,16] and bleomycin induced injury and inflammation [26] are increased in F508del CFTR (d/d mice), and since the IL-1R1 pathway is involved [20, 27] and required for the development of bleomycin-induced fibrosis [20], we studied the role of the Interleukin 1b (IL-1b) pathway in the response to inflammation and lung damage in F508del CFTR mice
The results suggest that in F508del CFTR mutant, the active IL-1b pathway is deleterious in response to repeated inflammatory injury
Summary
Cystic fibrosis (CF) is an autosomal recessive genetic disease that affects 1 newborn out of 3,500 in the USA (WHO), and 1 per 2,000–3,000 in Europe, with an average 40-year life expectancy. This pathology is caused by mutations within the gene encoding the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) chloride channel [1]. CF lungs display excessive inflammatory response, especially with increased neutrophil recruitment [8], the mechanism of this phenomenon is not adequately explained. Intervention in this process likely will benefit CF patients
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