Spontaneous DNA Extracellular Trap Formation and Th2-biased Immune Responses in Cystic Fibrosis-like Airways of Mice with Lung-specific Nedd4-2 Ubiquitin Ligase Deletion

Extracellular DNA exerts major pathological effects in cystic fibrosis (CF) airways. However, the cause for increased DNA and the contribution of neutrophil extracellular traps (NETs) in cystic fibrosis (CF) airways is uncertain. Additionally, suitable mouse models to study CF lung disease are lacking. We investigated the inflammatory profile and the presence of NETs in a novel mouse model with cystic fibrosis-like lung disease (Nedd4L lung-specific knockout; NL-KO). Our studies show that NL-KO mice have a Th2-biased background inflammation, spontaneous leukocyte infiltration and NET formation in their airways. Overall, inflammatory changes in NL-KO mouse airways occur age-dependently and spontaneously in the absence of detectable infection. Furthermore, NL-KO mice challenged with LPS and P. aeruginosa have an exacerbated inflammatory profile and impaired bacterial clearance, respectively. In conclusion, we show the relevance of NL-KO mouse model to study inflammation, infection, and the role of NETs in CF-like lung disease.MAS