Abstract
ObjectivesCommunity-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.MethodsWe 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.ResultsWe 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.ConclusionsOur 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.
Highlights
The prevalence of community-acquired Staphylococcus aureus pneumonia is low, but the disease can be very severe, with lethality higher than 40% in children and young adults [1,2]
Kineret/IL-1 receptor antagonist (IL-1Ra) blocks the IL-1b/IL-8 inflammatory cascade observed in a co-culture of human macrophages and lung epithelial cells exposed to S. aureus supernatant, but has no effect on Panton Valentine Leukocidin (PVL)-mediated neutrophil response
This result indicates that other staphylococcal secreted factors besides PVL can trigger the IL-1/IL-8 cascade. These results suggested that the majority of IL-8 produced early on during infection with S. aureus could be secondary to IL-1 production triggered by the exposure of macrophages to PVL or other staphylococcal secreted factors
Summary
The prevalence of community-acquired Staphylococcus aureus pneumonia is low, but the disease can be very severe, with lethality higher than 40% in children and young adults [1,2]. Due to the spread of community-acquired methicillin-resistant S. aureus (CAMRSA) and the increased resistance of these strains to antibiotics, it is crucial to understand the pathophysiological mechanisms at play during severe CA-S. aureus pneumonia and to find novel therapeutic options. PVL is very cytotoxic to human neutrophils, monocytes and macrophages. PVL triggers the production of IL-8 [3] by neutrophils and of IL-. IL-1b and IL8 are key cytokines to recruit neutrophils [6]. This inflammatory cascade could contribute to acute lung inflammation observed during infection. Diep et al demonstrated that PVL was associated with increased inflammation and neutrophil recruitment, both of which trigger lung injury [7]
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