RESUMEN
A hallmark feature of inflammation is the orchestrated recruitment of neutrophils from the bloodstream into inflamed tissue. Although selectins and integrins mediate recruitment in many tissues, they have a minimal role in the lungs and liver. Exploiting an unbiased in vivo functional screen, we identified a lung and liver homing peptide that functionally abrogates neutrophil recruitment to these organs. Using biochemical, genetic, and confocal intravital imaging approaches, we identified dipeptidase-1 (DPEP1) as the target and established its role as a physical adhesion receptor for neutrophil sequestration independent of its enzymatic activity. Importantly, genetic ablation or functional peptide blocking of DPEP1 significantly reduced neutrophil recruitment to the lungs and liver and provided improved survival in models of endotoxemia. Our data establish DPEP1 as a major adhesion receptor on the lung and liver endothelium and identify a therapeutic target for neutrophil-driven inflammatory diseases of the lungs.
Asunto(s)
Dipeptidasas/metabolismo , Neutrófilos/fisiología , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Animales , Cilastatina/farmacología , Cilastatina/uso terapéutico , Dipeptidasas/antagonistas & inhibidores , Dipeptidasas/genética , Modelos Animales de Enfermedad , Endotoxemia/mortalidad , Endotoxemia/patología , Endotoxemia/prevención & control , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Hígado/inmunología , Hígado/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones SCID , Infiltración Neutrófila/efectos de los fármacos , Péptidos/síntesis química , Péptidos/química , Péptidos/farmacología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Chronic hypersensitivity pneumonitis is characterized by pulmonary inflammation and fibrosis in response to repeated inhalation of mainly organic antigens. It is recognized that IL-17A is crucial for the development of pulmonary inflammation in murine models of experimental hypersensitivity pneumonitis, but its role in the development of pulmonary fibrosis has not been determined. Furthermore, the main cell type(s) that produce IL-17A in experimental hypersensitivity pneumonitis have not yet been identified. OBJECTIVE: Our objectives were to test the hypothesis that IL-17A plays a central role in the development of pulmonary fibrosis in experimental hypersensitivity pneumonitis and to determine the main inflammatory cell type(s) responsible for IL-17A production. METHODS: We used a mouse model of experimental hypersensitivity pneumonitis in which IL-17A was inhibited or neutrophils were depleted. We also used IL-17RA-deficient and RAG-2-deficient mice. Lung IL-17A-producing cells were identified by fluorescence-activated cell sorting of myeloid versus lymphoid cell populations, intracellular IL-17A staining, flow cytometry, and quantitative reverse transcription PCR for IL-17A mRNA. RESULTS: We found that the development of pulmonary fibrosis depended on IL-17A and was significantly attenuated by neutrophil depletion. Neutrophils and monocytes/macrophages were the main cell types that expressed IL-17A in our model. CONCLUSIONS: We have identified the central roles of IL-17A and neutrophils in the pathogenesis of fibrosis in experimental hypersensitivity pneumonitis. We have also established that nonlymphocytic innate immune cells, specifically neutrophils and monocytes/macrophages, rather than TH17 lymphocytes, are the predominant source of IL-17A in experimental hypersensitivity pneumonitis.