Type 2 inflammatory response protects against Staphylococcus aureus-induced sepsis

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Abstract Sepsis is defined as new organ dysfunction due to acute infection and has a mortality rate >20%. Recent studies indicate that type 2 cytokines, best known for their role in allergies, may be beneficial to the host during sepsis. We hypothesized that these responses protect against mortality during Staphylococcus aureus (S. aureus) induced sepsis. We tested this hypothesis in 2 different mouse models, using either house dust-mite (HDM) sensitization and challenge to activate an adaptive type 2 response, or pre-treatment with IL-33 via intratracheal instillation to induce an innate type 2 response. This was followed by intravenous infection with S. aureus to induce sepsis. Pre-treatment with either HDM or IL-33 protected against S. aureus-induced mortality, indicating that activation of type 2 responses is beneficial during acute infection. Analysis of lung immune cell populations by flow cytometry revealed increased levels of type 2 innate lymphoid cells (ILC2) in mice pre-treated with HDM or IL-33 compared to untreated controls. Further, we found a relative decrease in lung neutrophils and an increase in lung eosinophils in type 2-stimulated compared to untreated mice, suggesting that type 2 responses may suppress an overwhelming neutrophilic response. However, systemic depletion of neutrophils prior to infection resulted in accelerated mortality compared to non-depleted mice, indicating that neutrophils are necessary to protect against S. aureus infection, and that augmented eosinophilia may confer protection against mortality. We conclude that the type 2 response is protective during sepsis, possibly due to the activity of ILC2s and a delicate balance of eosinophils and neutrophils in the inflamed lung.