title: Activation of inflammasome signaling mediates pathology of acute P. aeruginosa pneumonia.
abstract: The respiratory tract is exceptionally well defended against infection from inhaled bacteria, with multiple proinflammatory signaling cascades recruiting phagocytes to clear airway pathogens. However, organisms that efficiently activate damaging innate immune responses, such as those mediated by the inflammasome and caspase-1, may cause pulmonary damage and interfere with bacterial clearance. The extracellular, opportunistic pathogen Pseudomonas aeruginosa expresses not only pathogen-associated molecular patterns that activate NF-κB signaling in epithelial and immune cells, but also flagella that activate the NLRC4 inflammasome. We demonstrate that induction of inflammasome signaling, ascribed primarily to the alveolar macrophage, impaired P. aeruginosa clearance and was associated with increased apoptosis/pyroptosis and mortality in a murine model of acute pneumonia. Strategies that limited inflammasome activation, including infection by fliC mutants, depletion of macrophages, deletion of NLRC4, reduction of IL-1β and IL-18 production, inhibition of caspase-1, and inhibition of downstream signaling in IL-1R- or IL-18R-null mice, all resulted in enhanced bacterial clearance and diminished pathology. These results demonstrate that the inflammasome provides a potential target to limit the pathological consequences of acute P. aeruginosa pulmonary infection.
authors.affiliation: Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Taylor S
authors.initials: TS
authors.lastname: Cohen
authors.forename: Alice S
authors.initials: AS
authors.lastname: Prince
mesh_terms: D000208:Acute Disease; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology; D005408:Flagellin / Q000276:immunology; D055786:Gene Knockout Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D054884:Host-Pathogen Interactions; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000502:physiology; D020381:Interleukin-17 / Q000378:metabolism; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009079:Mucociliary Clearance; D009504:Neutrophils / Q000276:immunology / Q000382:microbiology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D058847:Inflammasomes; D020381:Interleukin-17; D020382:Interleukin-18; D053583:Interleukin-1beta; C512299:Ipaf protein, mouse; D004002:Clodronic Acid; D005408:Flagellin; D016899:Interferon-beta; D016178:Granulocyte-Macrophage Colony-Stimulating Factor