摘要
Distinct neutrophil populations arise during certain pathological conditions.The generation of dysfunctional neutrophils during sepsis and their contribution to septicemia-related systemic immune suppression remain unclear.In this study,using an experimental sepsis model that features immunosuppression,we identified a novel population of pathogenic CD200R^(high) neutrophils that are generated during the initial stages of sepsis and contribute to systemic immune suppression by enhancing regulatory T(T_(reg))cells.Compared to their CD200R^(low)counterparts,sepsis-generated CD200Rhigh neutrophils exhibit impaired autophagy and dysfunction,with reduced chemotactic migration,superoxide anion production,and TNF-αproduction.Increased soluble CD200 blocks autophagy and neutrophil maturation in the bone marrow during experimental sepsis,and recombinant CD200 treatment in vitro can induce neutrophil dysfunction similar to that observed in CD200R^(high) neutrophils.The administration of anα-CD200R antibody effectively reversed neutrophil dysfunction by enhancing autophagy and protecting against a secondary infection challenge,leading to increased survival.Transcriptome analysis revealed that CD200R^(high) neutrophils expressed high levels of Igf1,which elicits the generation of Treg cells,while the administration of anα-CD200R antibody inhibited Treg cell generation in a secondary infection model.Taken together,our findings revealed a novel CD200R^(high) neutrophil population that mediates the pathogenesis of sepsis-induced systemic immunosuppression by generating Treg cells.
基金
supported by Basic Science Research Program(NRF-2020M3A9D3038435,NRF-2017R1A5A1014560)
the Korea Initiative for Fostering the University of Research and Innovation Program(NRF-2020M3H1A1077095)
through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT and Future Planning and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI)
funded by the Ministry of Health&Welfare,Republic of Korea(grant number:HI22C2004).
