Abstract
Excessive lung inflammation and airway epithelium damage are hallmarks of cystic fibrosis (CF) disease. It is unclear whether lung inflammation is related to an intrinsic defect in the immune response or to chronic infection. We aimed to determine whether TLR5-mediated response is defective in the CF airway epithelium. We used a newborn CF pig model to study intrinsic alterations in CF airway epithelium innate immune response. Airway epithelial cells (AECs) were stimulated with flagellin or lipopolysaccharide to determine responses specific for TLR5 and TLR4, respectively. We observed a significant increase in cytokine secretion when CF AECs were stimulated with flagellin compared to wild type (WT) AECs. These results were recapitulated when AECs were treated with an inhibitor of CFTR channel activity. We show that TLR5-signalling is altered in CF lung epithelium at birth. Modulation of TLR5 signalling could contribute to better control the excessive inflammatory response observed in CF lungs.
Highlights
Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is a recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, rendering the protein non-functional [1]
Flagellin induces an inflammatory response in airway epithelial cells that is exacerbated in cystic fibrosis
We observed that inhibition of CFTR activity with GlyH-101 upregulated the expression of genes coding for inflammatory cytokines (CCL2, CXCL2) and regulation of the immune response (NFKBIA, NFKBIE) after flagellin administration (Fig. 1A)
Summary
Cystic fibrosis (CF), the most common lethal genetic disease in the Caucasian population, is a recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, rendering the protein non-functional [1]. It is characterized by chronic bacterial infection, mainly Pseudomonas aeruginosa, persistent inflammation with exacerbated recruitment of polymorphonuclear neutrophils (PMNs) into the lungs, excessive release of proteases and lung tissue destruction [1]. Ways inflammation in naive, non-infected lungs [4] Their immune response upon a bacterial challenge seems to be altered facilitating lung colonization by the pathogen and a pro-inflammatory lung environment [6]
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