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

Abstract

OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Delphine Labrousse, Magali Perret, Davy Hayez, Sonia Da Silva, Cédric Badiou, Florence Couzon, Michèle Bes, Pascal Chavanet, Gérard Lina, François Vandenesch, Delphine Croisier-Bertin, Thomas Henry
• Journal: PloS one (PLoS One) Vol. 9 Issue 6 Pg. e97546 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24905099 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Toxins
• Exotoxins
• Inflammasomes
• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1beta
• Interleukin-8
• Leukocidins
• Panton-Valentine leukocidin

Topics

• Animals
• Bacterial Toxins (toxicity)
• Exotoxins (toxicity)
• Inflammasomes (drug effects, immunology)
• Interleukin 1 Receptor Antagonist Protein (pharmacology, therapeutic use)
• Interleukin-1beta (metabolism)
• Interleukin-8 (metabolism)
• Leukocidins (toxicity)
• Macrophages (drug effects, immunology)
• Pneumonia, Staphylococcal (drug therapy, etiology, metabolism)
• Rabbits