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Pseudomonas aeruginosa type-3 secretion system dampens host defense by exploiting the NLRC4-coupled inflammasome.

Pseudomonas aeruginosa type-3 secretion system dampens host defense by exploiting the NLRC4-coupled inflammasome.

Authors :
Faure E
Mear JB
Faure K
Normand S
Couturier-Maillard A
Grandjean T
Balloy V
Ryffel B
Dessein R
Chignard M
Uyttenhove C
Guery B
Gosset P
Chamaillard M
Kipnis E
Source :
American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2014 Apr 01; Vol. 189 (7), pp. 799-811.
Publication Year :
2014

Abstract

Rationale: 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.<br />Objectives: We sought to determine the underlying mechanisms of this effect of the activation of NLRC4 by P. aeruginosa.<br />Methods: 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.<br />Measurements and Main Results: 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.<br />Conclusions: 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.

Details

Language :
English
ISSN :
1535-4970
Volume :
189
Issue :
7
Database :
MEDLINE
Journal :
American journal of respiratory and critical care medicine
Publication Type :
Academic Journal
Accession number :
24555512
Full Text :
https://doi.org/10.1164/rccm.201307-1358OC