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Pseudomonas aeruginosa Type-3 Secretion System Dampens Host Defense by Exploiting the NLRC4-coupled Inflammasome

2014; American Thoracic Society; Volume: 189; Issue: 7 Linguagem: Inglês

10.1164/rccm.201307-1358oc

1535-4970

Emmanuel Faure, Jean-Baptiste Méar, Karine Faure, Sylvain Normand, Aurélie Couturier-Maillard, Teddy Grandjean, Viviane Balloy, Bernhard Ryffel, Rodrigue Dessein, Michel Chignard, Catherine Uyttenhove, Benoît Guéry, Philippe Gosset, Mathias Chamaillard, Éric Kipnis,

Inflammasome and immune disorders

Pseudomonas aeruginosa, a major problem pathogen responsible for severe infections in critically ill patients, triggers, through a functional type-3 secretion system (T3SS), the activation of an intracellular cytosolic sensor of innate immunity, NLRC4. Although the NLRC4-inflammasome-dependent response contributes to increased clearance of intracellular pathogens, it seems that NLRC4 inflammasome activation decreases the clearance of P. aeruginosa, a mainly extracellular pathogen.We sought to determine the underlying mechanisms of this effect of the activation of NLRC4 by P. aeruginosa.We established acute lung injury in wild-type and Nlrc4(-/-) mice using sublethal intranasal inocula of P. aeruginosa strain CHA expressing or not a functional T3SS. We studied 96-hour survival, lung injury, bacterial clearance from the lungs, cytokine secretion in bronchoalveolar lavage, lung antimicrobial peptide expression by quantitative polymerase chain reaction, and flow cytometry analysis of lung cells.Nlrc4(-/-) mice showed enhanced bacterial clearance and decreased lung injury contributing to increased survival against extracellular P. aeruginosa strain expressing a functional T3SS. The mechanism involved decreased NLRC4-inflammasome-driven IL-18 secretion attenuating lung injury caused by excessive neutrophil recruitment. Additionally, in the lungs of Nlrc4(-/-) mice secretion of IL-17 by innate immune cells was increased and responsible for increased expression of lung epithelial antimicrobial peptides. Furthermore, IL-18 secretion was found to repress IL-17 and IL-17-driven lung antimicrobial peptide expression.We report a new role of the T3SS apparatus itself, independently of exotoxin translocation. Through NLRC4 inflammasome activation, the T3SS promotes IL-18 secretion, which dampens a beneficial IL-17-mediated antimicrobial host response.