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Role of IL-1ß in experimental cystic fibrosis upon P. aeruginosa infection.

Palomo, Jennifer; Marchiol, Tiffany; Piotet, Julie; Fauconnier, Louis; Robinet, Marieke; Reverchon, Flora; Le Bert, Marc; Togbe, Dieudonnée; Buijs-Offerman, Ruvalic; Stolarczyk, Marta; Quesniaux, Valérie F J; Scholte, Bob J; Ryffel, Bernhard.
PLoS One; 9(12): e114884, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25500839
Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1ß 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-1ß and TNF-α in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1ß signaling in response to P. aeruginosa. IL-1ß 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-1ß antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1ß production and reduced bacterial clearance. Further, we show that neutralization of IL-1ß 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-1ß pathway may be detrimental in CF patients.
Selo DaSilva