Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 48, Issue 10, Pages 1707-1716Publisher
WILEY
DOI: 10.1002/eji.201847556
Keywords
IL-1 activation; Inflammasome; Lung infection; Staphylococcus aureus; Type III interferon
Categories
Funding
- American Association of Immunologists Careers in Immunology Fellowship Program
- NIH [R56HL125653, R01HL134870]
- Office of the Director, National Institutes of Health [S10RR027050]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL134870] Funding Source: NIH RePORTER
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Maintaining balanced levels of IL-1 is extremely important to avoid host tissue damage during infection. Our goal was to understand the mechanisms behind the reduced pathology and decreased bacterial burdens in Ifnlr1(-/-) mice during lung infection with Staphylococcus aureus. Intranasal infection of Ifnlr1(-/-) mice with S.aureus led to significantly improved bacterial clearance, survival and decrease of proinflammatory cytokines in the airway including IL-1. Ifnlr1(-/-) mice treated with recombinant IL-1 displayed increased bacterial burdens in the airway and lung. IL-1 levels in neutrophils from Ifnlr1(-/-) infected mice lungs were decreased when compared to neutrophils from WT mice. Mice lacking NLRP3 and caspase-1 had reduced IL-1 levels 4h after infection, due to reductions or absence of active caspase-1 respectively, but levels at 24h were comparable to WT infected mice. Ifnlr1(-/-) infected mice had decreases in both active caspase-1 and neutrophil elastase indicating an important role for the neutrophil serine protease in IL-1 processing. By inhibiting neutrophil elastase, we were able to decrease IL-1 levels by 39% in Nlrp3(-/-) infected mice when compared to WT mice. These results highlight the crucial role of both proteases in IL-1 processing, via inflammasome-dependent and -independent mechanisms.
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