Sepsis-induced lung injury develops due to an inappropriate inflammatory response to infection leading to a compromised alveolar barrier. While this detrimental response remains poorly understood, we recently demonstrated that activation of a pulmonary type 2 immune response via IL-33 treatment prior to lethal blood stream infection with Staphylococcus aureus(S. aureus) protects against mortality in mice. However, the ability of pulmonary IL-33 to protect against bacterial pneumonia-associated lung injury remained unknown. We hypothesized that IL-33-induced type 2 pulmonary responses would protect against acute lung injury associated with S. aureus pulmonary infection.Methods: C57BL/6 mice were treated intratracheally with the type 2-initiating cytokine IL-33 for 3 days followed by lethal intratracheal infection with S. aureusUSA300. Flow cytometry and multiplex cytokine analysis were used to evaluate the immune response in bronchioalveolar lavage (BAL) and lung digests. Lung injury was assessed by quantifying levels of BAL albumin, lung permeability, pulmonary edema, and oxygen saturation.Results: IL-33 treatment prior to lethal S. aureus pulmonary infection promoted survival compared to PBS controls. Flow cytometry analysis of BAL at 18 and 36 hours after infection revealed that IL-33 pretreatment induced eosinophilia, but also reduced the neutrophilia associated with acute bacterial infection. Cytokine multiplex analysis of the BAL indicated that IL-33 pretreatment suppressed S. aureus-induced proinflammatory cytokine release, particularly G-CSF and IFN-γ . IL-33 pretreatment also inhibited S. aureus-induced lung injury, with lower levels of BAL albumin, serum FITC-dextran, and pulmonary edema, and an associated increase in oxygen saturation. Depletion of eosinophils eliminated IL-33 mediated protection against mortality and inhibition of neutrophilia.Conclusion: Activation of pulmonary eosinophilia via IL-33 protects against lethal S. aureus pneumonia and is associated with suppression of pulmonary proinflammatory responses and reduction of lung injury. These data reveal a novel role for eosinophils in pulmonary alveolar barrier maintenance and suggest that modulation of pulmonary type 2 immunity may represent a therapeutic strategy for improving the outcomes of lethal sepsis-induced lung injury.
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