title: Pseudomonas aeruginosa type-3 secretion system dampens host defense by exploiting the NLRC4-coupled inflammasome.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  We sought to determine the underlying mechanisms of this effect of the activation of NLRC4 by P. aeruginosa.
  
  
  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.
  
  
  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.
  
  
  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.
authors.affiliation: 1 Pseudomonas aeruginosa Host-Pathogen Translational Research Group, Université Droit et Santé de Lille, Lille, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Faure
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Mear
authors.forename: Karine
authors.initials: K
authors.lastname: Faure
authors.forename: Sylvain
authors.initials: S
authors.lastname: Normand
authors.forename: Aurélie
authors.initials: A
authors.lastname: Couturier-Maillard
authors.forename: Teddy
authors.initials: T
authors.lastname: Grandjean
authors.forename: Viviane
authors.initials: V
authors.lastname: Balloy
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Rodrigue
authors.initials: R
authors.lastname: Dessein
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.forename: Catherine
authors.initials: C
authors.lastname: Uyttenhove
authors.forename: Benoit
authors.initials: B
authors.lastname: Guery
authors.forename: Philippe
authors.initials: P
authors.lastname: Gosset
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.forename: Eric
authors.initials: E
authors.lastname: Kipnis
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011552:Pseudomonas Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000378:metabolism / Q000472:pathogenicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D020381:Interleukin-17; D020382:Interleukin-18; C512299:Ipaf protein, mouse; D020170:Caspase 1