title: A crucial role of Flagellin in the induction of airway mucus production by Pseudomonas aeruginosa.
abstract: Pseudomonas aeruginosa is an opportunistic pathogen involved in nosocomial infections. Flagellin is a P. aeruginosa virulence factor involved in host response to this pathogen. We examined the role of flagellin in P. aeruginosa-induced mucus secretion. Using a mouse model of pulmonary infection we showed that PAK, a wild type strain of P. aeruginosa, induced airway mucus secretion and mucin muc5ac expression at higher levels than its flagellin-deficient mutant (ΔFliC). PAK induced expression of MUC5AC and MUC2 in both human airway epithelial NCI-H292 cell line and in primary epithelial cells. In contrast, ΔFliC infection had lower to no effect on MUC5AC and MUC2 expressions. A purified P. aeruginosa flagellin induced MUC5AC expression in parallel to IL-8 secretion in NCI-H292 cells. Accordingly, ΔFliC mutant stimulated IL-8 secretion at significantly lower levels compared to PAK. Incubation of NCI-H292 cells with exogenous IL-8 induced MUC5AC expression and pre-incubation of these cells with an anti-IL-8 antibody abrogated flagellin-mediated MUC5AC expression. Silencing of TLR5 and Naip, siRNA inhibited both flagellin-induced MUC5AC expression and IL-8 secretion. Finally, inhibition of ERK abolished the expression of both PAK- and flagellin-induced MUC5AC. We conclude that: (i) flagellin is crucial in P. aeruginosa-induced mucus hyper-secretion through TLR5 and Naip pathways; (ii) this process is mediated by ERK and amplified by IL-8. Our findings help understand the mechanisms involved in mucus secretion during pulmonary infectious disease induced by P. aeruginosa, such as in cystic fibrosis.
authors: Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France. fatima.ben-mohamed@pasteur.fr
authors: Fatima
authors: F
authors: Ben Mohamed
authors: Fatima Ben
authors: FB
authors: Mohamed
authors: Ignacio
authors: I
authors: Garcia-Verdugo
authors: Mathieu
authors: M
authors: Medina
authors: Viviane
authors: V
authors: Balloy
authors: Michel
authors: M
authors: Chignard
authors: Reuben
authors: R
authors: Ramphal
authors: Lhousseine
authors: L
authors: Touqui
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D005408:Flagellin / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D055271:Mucin 5AC / Q000096:biosynthesis / Q000276:immunology; D055262:Mucin-2 / Q000096:biosynthesis / Q000276:immunology; D009093:Mucus / Q000276:immunology / Q000378:metabolism*; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000276:immunology / Q000378:metabolism; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000276:immunology / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; C524626:Muc2 protein, mouse; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D055262:Mucin-2; C496800:NAIP protein, human; D051616:Neuronal Apoptosis-Inhibitory Protein; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin