The deficiency in IL-1R1 apparently protected the mice against LPSinduced mortality in d/d mice. P.aeruginosa-LPS challenges were responsible for leucocyte recruitment, including neutrophils. Despite increased cell infiltration in the lung of d/d mice, collagen deposition and mucus production were only slightly increased after multiple LPS challenges. Repeated LPS challenges did not cause epithelial damage and chronic inflammation, which we explain by tolerance induction, that is the reason to switch to P. aeruginosa infection. No spontaneous inflammation was found in young adult F508del CFTR mutant on C57BL/6 genetic background under our conditions. Whereas signs of inflammation and tissue remodeling develop early in most CF patients, in murine models are variable. These data are consistent with published data on the absence of spontaneous pathology such as mucus plugging, neutrophil accumulation or bronchiectasis, in young mice deficient or mutated for the Cftr gene, but neutrophilic inflammation has been reported in absence of infection. Spontaneous lung pathology development seems to be dependent on the age of mice, genetic background and animal facility health status. However, in CF mutant mice challenged with pro-inflammatory agents enhanced injury and inflammation compared to wild type was reported in several independent studies. Therefore, to get closer to a model of lung infections that occur in CF patients, we used an acute P. aeruginosa infection model, which is the most current pathogen found in CF patient, in F508del CFTR mice. Twenty hours after P. aeruginosa infection, d/d mice displayed increased neutrophil recruitment in BALF as compared with WT mice. They also showed an increase in bacterial load and cytokine production, such as IL-1b and TNF-a, in BALF. These results suggest a higher sensitivity to infection in d/d mice, consistent with previous studies in CFTR mutant mice, showing an augmentation of bacterial load and production of pro-inflammatory cytokines after P. aeruginosa infection. The enhanced production of IL-1b compared to WT after infection was associated with increased epithelial damage, cell infiltration and CFU. Then, we analyzed the effect of IL-1b neutralization at steady state in the lung. We found that in d/d as well as in WT mice, IL-1b antibody had no significant effect on Palbociclib CDK inhibitor survival. Furthermore d/d and WT mice displayed no difference in basal Il1b mRNA expression, and repeated anti-IL-1b antibody administration had no significant effect on basal inflammatory parameters and cytokine production. However, our data suggest that IL-1b may cause an excessive and pathologic inflammation in challenged CF mutant lungs. IL-1b over-expression in d/d mice infected with P. aeruginosa was accompanied by a higher bacterial load. Indeed, excessive production of inflammatory cytokines has been associated with bacterial persistence in other studies as well. High concentrations of cytokine, such as IL1b, IL-6 or TNF-a, enhance intracellular and extracellular bacterial growth of P. aeruginosa, or S. aureus in the presence of monocytes.