Kineret®/IL-1ra blocks the IL-1/IL-8 inflammatory cascade during recombinant Panton Valentine Leukocidin-triggered pneumonia but not during S. aureus infection

Community-acquired Staphylococcus aureus necrotizing pneumonia is a life-threatening disease. Panton Valentine Leukocidin (PVL) has been associated with necrotizing pneumonia. PVL triggers inflammasome activation in human macrophages leading to IL-1β release. IL-1β activates lung epithelial cells to...

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Veröffentlicht in:PloS one 2014-06, Vol.9 (6), p.e97546
Hauptverfasser: Labrousse, Delphine, Perret, Magali, Hayez, Davy, Da Silva, Sonia, Badiou, Cédric, Couzon, Florence, Bes, Michèle, Chavanet, Pascal, Lina, Gérard, Vandenesch, François, Croisier-Bertin, Delphine, Henry, Thomas
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container_volume 9
creator Labrousse, Delphine
Perret, Magali
Hayez, Davy
Da Silva, Sonia
Badiou, Cédric
Couzon, Florence
Bes, Michèle
Chavanet, Pascal
Lina, Gérard
Vandenesch, François
Croisier-Bertin, Delphine
Henry, Thomas
description Community-acquired Staphylococcus aureus necrotizing pneumonia is a life-threatening disease. Panton Valentine Leukocidin (PVL) has been associated with necrotizing pneumonia. PVL triggers inflammasome activation in human macrophages leading to IL-1β release. IL-1β activates lung epithelial cells to release IL-8. This study aimed to assess the relevance of this inflammatory cascade in vivo and to test the potential of an IL-1 receptor antagonist (IL-1Ra/Kineret) to decrease inflammation-mediated lung injury. We used the sequential instillation of Heat-killed S. aureus and PVL or S. aureus infection to trigger necrotizing pneumonia in rabbits. In these models, we investigated inflammation in the presence or absence of IL-1Ra/Kineret. We demonstrated that the presence of PVL was associated with IL-1β and IL-8 release in the lung. During PVL-mediated sterile pneumonia, Kineret/IL-1Ra reduced IL-8 production indicating the relevance of the PVL/IL-1/IL-8 cascade in vivo and the potential of Kineret/IL-1Ra to reduce lung inflammation. However, Kineret/IL-1Ra was ineffective in blocking IL-8 production during infection with S. aureus. Furthermore, treatment with Kineret increased the bacterial burden in the lung. Our data demonstrate PVL-dependent inflammasome activation during S.aureus pneumonia, indicate that IL-1 signaling controls bacterial burden in the lung and suggest that therapy aimed at targeting this pathway might be deleterious during pneumonia.
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Panton Valentine Leukocidin (PVL) has been associated with necrotizing pneumonia. PVL triggers inflammasome activation in human macrophages leading to IL-1β release. IL-1β activates lung epithelial cells to release IL-8. This study aimed to assess the relevance of this inflammatory cascade in vivo and to test the potential of an IL-1 receptor antagonist (IL-1Ra/Kineret) to decrease inflammation-mediated lung injury. We used the sequential instillation of Heat-killed S. aureus and PVL or S. aureus infection to trigger necrotizing pneumonia in rabbits. In these models, we investigated inflammation in the presence or absence of IL-1Ra/Kineret. We demonstrated that the presence of PVL was associated with IL-1β and IL-8 release in the lung. During PVL-mediated sterile pneumonia, Kineret/IL-1Ra reduced IL-8 production indicating the relevance of the PVL/IL-1/IL-8 cascade in vivo and the potential of Kineret/IL-1Ra to reduce lung inflammation. 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Michèle</au><au>Chavanet, Pascal</au><au>Lina, Gérard</au><au>Vandenesch, François</au><au>Croisier-Bertin, Delphine</au><au>Henry, Thomas</au><au>Rooijakkers, Suzan H. M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kineret®/IL-1ra blocks the IL-1/IL-8 inflammatory cascade during recombinant Panton Valentine Leukocidin-triggered pneumonia but not during S. aureus infection</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-06-06</date><risdate>2014</risdate><volume>9</volume><issue>6</issue><spage>e97546</spage><pages>e97546-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Community-acquired Staphylococcus aureus necrotizing pneumonia is a life-threatening disease. Panton Valentine Leukocidin (PVL) has been associated with necrotizing pneumonia. PVL triggers inflammasome activation in human macrophages leading to IL-1β release. IL-1β activates lung epithelial cells to release IL-8. This study aimed to assess the relevance of this inflammatory cascade in vivo and to test the potential of an IL-1 receptor antagonist (IL-1Ra/Kineret) to decrease inflammation-mediated lung injury. We used the sequential instillation of Heat-killed S. aureus and PVL or S. aureus infection to trigger necrotizing pneumonia in rabbits. In these models, we investigated inflammation in the presence or absence of IL-1Ra/Kineret. We demonstrated that the presence of PVL was associated with IL-1β and IL-8 release in the lung. During PVL-mediated sterile pneumonia, Kineret/IL-1Ra reduced IL-8 production indicating the relevance of the PVL/IL-1/IL-8 cascade in vivo and the potential of Kineret/IL-1Ra to reduce lung inflammation. However, Kineret/IL-1Ra was ineffective in blocking IL-8 production during infection with S. aureus. Furthermore, treatment with Kineret increased the bacterial burden in the lung. Our data demonstrate PVL-dependent inflammasome activation during S.aureus pneumonia, indicate that IL-1 signaling controls bacterial burden in the lung and suggest that therapy aimed at targeting this pathway might be deleterious during pneumonia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24905099</pmid><doi>10.1371/journal.pone.0097546</doi><orcidid>https://orcid.org/0000-0002-0687-8565</orcidid><orcidid>https://orcid.org/0000-0001-9412-7106</orcidid><orcidid>https://orcid.org/0000-0002-9236-7998</orcidid><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
ispartof PloS one, 2014-06, Vol.9 (6), p.e97546
issn 1932-6203
1932-6203
language eng
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subjects Activation
Animals
Antimicrobial agents
Bacteria
Bacterial Toxins - toxicity
Bacteriology
Biology and Life Sciences
Cell activation
Epithelial cells
Exotoxins - toxicity
Hospitals
Immunology
In vivo methods and tests
Infections
Infectious diseases
Inflammasomes
Inflammasomes - drug effects
Inflammasomes - immunology
Inflammation
Interleukin 1
Interleukin 1 receptor antagonist
Interleukin 1 Receptor Antagonist Protein - pharmacology
Interleukin 1 Receptor Antagonist Protein - therapeutic use
Interleukin 8
Interleukin-1beta - metabolism
Interleukin-8 - metabolism
Leukocidin
Leukocidins - toxicity
Life Sciences
Lungs
Macrophages
Macrophages - drug effects
Macrophages - immunology
Medicine and Health Sciences
Microbiology and Parasitology
Neutrophils
Pneumonia
Pneumonia, Staphylococcal - drug therapy
Pneumonia, Staphylococcal - etiology
Pneumonia, Staphylococcal - metabolism
Rabbits
Research and Analysis Methods
Signaling
Staphylococcus aureus
Staphylococcus infections
Systematic review
Virology
title Kineret®/IL-1ra blocks the IL-1/IL-8 inflammatory cascade during recombinant Panton Valentine Leukocidin-triggered pneumonia but not during S. aureus infection
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