Airway Administration of Flagellin Regulates the Inflammatory Response to Pseudomonas aeruginosa.
Raquel López-GálvezIsabelle FleurotPablo ChameroSascha TrappMichel OlivierClaire ChevaleyreCéline BarcMickael RiouChristelle RossignolAntoine GuillonMustapha Si-TaharTobias MayPascal BarbryAndrea BährNikolai KlymiukJean-Claude SirardIgnacio CaballeroPublished in: American journal of respiratory cell and molecular biology (2021)
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.
Keyphrases
- cystic fibrosis
- pseudomonas aeruginosa
- toll like receptor
- immune response
- inflammatory response
- oxidative stress
- nuclear factor
- endothelial cells
- lung function
- lps induced
- signaling pathway
- poor prognosis
- infectious diseases
- staphylococcus aureus
- escherichia coli
- cell proliferation
- antimicrobial resistance
- chronic obstructive pulmonary disease
- multidrug resistant
- intensive care unit
- weight loss
- amino acid
- high glucose
- single molecule
- reactive oxygen species
- acute respiratory distress syndrome
- gram negative