IL-1β activation in response to Staphylococcus aureus lung infection requires inflammasome-dependent and independent mechanisms.

Maintaining balanced levels of IL-1β 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-1β. Ifnlr1-/- mice treated with recombinant IL-1β displayed increased bacterial burdens in the airway and lung. IL-1β 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-1β levels 4 h after infection, due to reductions or absence of active caspase-1 respectively, but levels at 24 h 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-1β processing. By inhibiting neutrophil elastase, we were able to decrease IL-1β levels by 39% in Nlrp3-/- infected mice when compared to WT mice. These results highlight the crucial role of both proteases in IL-1β processing, via inflammasome-dependent and -independent mechanisms.