Pulmonary innate type 2 inflammatory responses protect against Staphylococcus aureus-induced sepsis

Abstract

Abstract Sepsis is defined as life-threatening organ dysfunction caused by the body’s response to infection. Sepsis is associated with overwhelming type 1 or type 17 immunologic inflammation, but the role of type 2 immune responses in sepsis remains unknown. To test the role of type 2 immune responses in sepsis, we treated mice with intratracheal IL-33 to induce an innate pulmonary type 2 response, followed by intravenous infection with S. aureus to induce sepsis. Surprisingly, type 2 responses were beneficial during acute infection, as IL-33 treatment protected mice from S. aureus-induced death. An increase in the ratio of lung eosinophils to neutrophils was revealed in IL-33 treated, S. aureus infected mice, suggesting that type 2 responses suppress lung neutrophilia. Further, no difference was found in splenic granulocytes or lymphocytes, indicating that activation of pulmonary immune responses alone was sufficient for protection. Infection of PLZF null mice, which have defective NKT and ILC2 cells normally required for type 2 innate responses after IL-33 treatment, resulted in accelerated mortality compared with wild type littermate controls. Moreover, IL-33 did not rescue PLZF null mice from death. However, infection of CD1d null mice, which lack only NKT cells but have intact ILC2s, demonstrated no difference in mortality. Thus, pulmonary type 2 innate immunity provided by ILC2s is critical for protection against S. aureus-mediated death.