RESUMO
Pneumonia-induced lung injury and acute respiratory distress syndrome can develop because of an inappropriate inflammatory response to acute infections, leading to a compromised alveolar barrier. Recent work suggests that hospitalized patients with allergies/asthma are less likely to die of pulmonary infections and that there is a correlation between survival from acute respiratory distress syndrome and higher eosinophil counts; thus, we hypothesized that eosinophils associated with a type 2 immune response may protect against pneumonia-induced acute lung injury. To test this hypothesis, mice were treated with the type 2-initiating cytokine IL-33 intratracheally 3 days before induction of pneumonia with airway administration of a lethal dose of Staphylococcus aureus. Interestingly, IL-33 pretreatment promoted survival by inhibiting acute lung injury: amount of BAL fluid proinflammatory cytokines and pulmonary edema were both reduced, with an associated increase in oxygen saturation. Pulmonary neutrophilia was also reduced, whereas eosinophilia was strongly increased. This eosinophilia was key to protection; eosinophil reduction eliminated both IL-33-mediated protection against mortality and inhibition of neutrophilia and pulmonary edema. Together, these data reveal a novel role for eosinophils in protection against lung injury and suggest that modulation of pulmonary type 2 immunity may represent a novel therapeutic strategy.
Assuntos
Lesão Pulmonar Aguda/imunologia , Eosinófilos/imunologia , Interleucina-33/imunologia , Pneumonia Estafilocócica/imunologia , Edema Pulmonar/imunologia , Síndrome do Desconforto Respiratório/imunologia , Staphylococcus aureus/patogenicidade , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/microbiologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Toxina Diftérica/farmacologia , Modelos Animais de Doenças , Eosinófilos/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Interleucina-33/genética , Interleucina-33/farmacologia , Interleucina-5/deficiência , Interleucina-5/genética , Interleucina-5/imunologia , Contagem de Leucócitos , Procedimentos de Redução de Leucócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Pneumonia Estafilocócica/complicações , Pneumonia Estafilocócica/microbiologia , Pneumonia Estafilocócica/mortalidade , Edema Pulmonar/complicações , Edema Pulmonar/microbiologia , Edema Pulmonar/mortalidade , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/microbiologia , Síndrome do Desconforto Respiratório/prevenção & controle , Staphylococcus aureus/imunologia , Análise de SobrevidaRESUMO
The dysregulated, unbalanced immune response of sepsis results in a mortality exceeding 20%, yet recent findings by our group indicate that patients with allergic, type 2-mediated immune diseases are protected from developing sepsis. We evaluated CD4+ Th cell polarization among patients with Staphylococcus aureus bacteremia and confirmed that survivors had a higher percentage of circulating Th2 cells but lower frequencies of Th17 cells and neutrophils early in the course of infection. To establish the mechanism of this protection, we used a mouse model of lethal S. aureus bacteremia and found that intratracheal pretreatment with the type 2-initiating cytokine IL-33 activated pulmonary type 2 innate lymphoid cells (ILC2s) and promoted eosinophilia. In addition, stimulation of type 2 immunity before lethal infection suppressed the pulmonary neutrophilic response to S. aureus. Mice lacking functional ILC2s did not respond to IL-33 and were not protected from lethal bacteremia, but treatment of these mice with the type 2 cytokines IL-5 and IL-13 rescued them from death. Depletion of eosinophils abrogated IL-33-mediated protection, indicating that eosinophilia is also necessary for the survival benefit. Thus, we have identified a potentially novel mechanism by which type 2 immunity can balance dysregulated septic inflammatory responses, thereby clarifying the protective benefit of type 2 immune diseases on sepsis mortality.