| First Author | Palomo J | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 12 | Pages | e114884 |
| PubMed ID | 25500839 | Mgi Jnum | J:225122 |
| Mgi Id | MGI:5691605 | Doi | 10.1371/journal.pone.0114884 |
| Citation | Palomo J, et al. (2014) Role of IL-1beta in experimental cystic fibrosis upon P. aeruginosa infection. PLoS One 9(12):e114884 |
| abstractText | Cystic fibrosis is associated with increased inflammatory responses to pathogen challenge. Here we revisited the role of IL-1beta 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-1beta and TNF-alpha in parenchyma as compared to WT mice. Thus, F508del-CFTR mice show enhanced IL-1beta signaling in response to P. aeruginosa. IL-1beta 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-1beta antibody neutralization. In conclusion, enhanced susceptibility to P. aeruginosa in d/d mice correlates with an excessive inflammation and with increased IL-1beta production and reduced bacterial clearance. Further, we show that neutralization of IL-1beta 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-1beta pathway may be detrimental in CF patients. |
