Excessive
lung inflammation and airway epithelial damage are hallmarks of human inflammatory
lung diseases, such as
cystic fibrosis (CF). Enhancement of innate immunity provides protection against pathogens while reducing lung-damaging
inflammation. However, the mechanisms underlying innate immunity-mediated protection in the lung remain mysterious, in part because of the lack of appropriate animal models for these human diseases. TLR5 (
Toll-like receptor 5) stimulation by its specific
ligand, the
bacterial protein flagellin, has been proposed to enhance protection against several respiratory
infectious diseases, although other cellular events, such as calcium signaling, may also control the intensity of the innate immune response. Here, we investigated the molecular events prompted by stimulation with
flagellin and its role in regulating innate immunity in the lung of the pig, which is anatomically and genetically more similar to humans than rodent models. We found that
flagellin treatment modulated NF-κB signaling and intracellular
calcium homeostasis in airway epithelial cells.
Flagellin pretreatment reduced the NF-κB nuclear translocation and the expression of proinflammatory
cytokines to a second
flagellin stimulus as well as to
Pseudomonas aeruginosa infection. Moreover, in vivo administration of
flagellin decreased the severity of P. aeruginosa-induced
pneumonia. Then we confirmed these beneficial effects of
flagellin in a pathological model of CF by using ex vivo precision-cut lung slices from a CF pigz model. These results provide evidence that
flagellin treatment contributes to a better regulation of the inflammatory response in inflammatory
lung diseases such as CF.