IL-17 primes airway epithelial cells lacking functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) to increase NOD1 responses

In Cystic Fibrosis (CF), the absence of functional Cystic Fibrosis Transmembrane conductance Regulator (CFTR) translates into chronic bacterial infection, excessive inflammation, tissue damage, imparied lung function and eventual death Understanding the mechanisms underlying this vicious circle of inflammation is key to better therapies for CIF In this manuscript. we have found that the presence of IL-17 in the airways of CIF patients not only exacerbates inflammation through the recruitment of neutrophils via secretion of CXCL8. but also by priming airway epithelial cells lacking functional CFTR to increase response to the bacterial sensor NOD1. IL-17 stimulation of airway epithelial cells (AECs) lacking functional CFTR increased the expression of NOD1, NOD2, TLR4 and its own receptors IL-17RA and IL-17RC Moreover. prior stimulation of AECs expressing the CFTR Delta F508 mutant with IL-17 showed Much greater CXCL8 secretion in response to a NOD1 agonist and Pseudomonas aeruginosa diffusible material Taken together our results show that IL-17 primes AECs expressing CFTR Delta F508 to increase host defence response to bacteria through the up-regulation of PRRs. and in particular of NOD1, and identifies another mechanism of action through which the CFTR Delta F508 Mutation leads to increase inflammation in response to bacterial ligands Therefore preventing IL-17 function in CF may prove an important strategy in decreasing lung inflammation due to both direct and indirect effects (C) 2009 Elsevier Inc All rights reserved