Liao Chaoxiong, Luo Shuhua, Liu Xiaolei, Zhang Lina, Xie Pengyun, Zhou Wending, Lu Yue, Zhong Hanhui, Zhang Xuedi, Xiong Ziying, Huang Xiao, Mo Guixi, Ma Daqing, Tang Jing
Department of Anesthesiology, Affiliated hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong, China.
Guangdong Medical University, Zhanjiang 524000, Guangdong, China.
Theranostics. 2024 Apr 8;14(6):2589-2604. doi: 10.7150/thno.93812. eCollection 2024.
The mechanisms underlying the increased mortality of secondary infections during the immunosuppressive phase of sepsis remain elusive. We sought to investigate the role of Siglec-F neutrophils on splenic T lymphocytes in the immunosuppressed phase of sepsis and on secondary infection in PICS mice, and to elucidate the underlying mechanisms. We established a mouse model of sepsis-induced immunosuppression followed by secondary infection with LPS or The main manifestation of immunosuppression is the functional exhaustion of splenic T lymphocytes. Treg depletion reagent Anti-IL-2, IL-10 blocker Anti-IL-10R, macrophage depletion reagent Liposomes, neutrophil depletion reagent Anti-Ly6G, neutrophil migration inhibitor SB225002, Siglec-F depletion reagent Anti-Siglec-F are all used on PICS mice. The function of neutrophil subsets was investigated by adoptive transplantation and the experiments in vitro. Compared to other organs, we observed a significant reduction in pro-inflammatory cytokines in the spleen, accompanied by a marked increase in IL-10 production, primarily by infiltrating neutrophils. These infiltrating neutrophils in the spleen during the immunosuppressive phase of sepsis undergo phenotypic change in the local microenvironment, exhibiting high expression of neutrophil biomarkers such as Siglec-F, Ly6G, and Siglec-E. Depletion of neutrophils or specifically targeting Siglec-F leads to enhance the function of T lymphocytes and a notable improvement in the survival of mice with secondary infections. We identified Siglec-F neutrophils as the primary producers of IL-10, which significantly contributed to T lymphocyte suppression represents a novel finding with potential therapeutic implications.
脓毒症免疫抑制阶段继发性感染死亡率增加的潜在机制仍不清楚。我们试图研究Siglec-F中性粒细胞在脓毒症免疫抑制阶段对脾脏T淋巴细胞以及对持续性重症感染（PICS）小鼠继发性感染的作用，并阐明其潜在机制。我们建立了脓毒症诱导免疫抑制的小鼠模型，随后用脂多糖或……进行继发性感染。免疫抑制的主要表现是脾脏T淋巴细胞功能耗竭。在PICS小鼠上使用Treg耗竭试剂抗IL-2、IL-10阻断剂抗IL-10R、巨噬细胞耗竭试剂脂质体、中性粒细胞耗竭试剂抗Ly6G、中性粒细胞迁移抑制剂SB225002、Siglec-F耗竭试剂抗Siglec-F。通过过继移植和体外实验研究中性粒细胞亚群的功能。与其他器官相比，我们观察到脾脏中促炎细胞因子显著减少，同时IL-10产生显著增加，主要由浸润的中性粒细胞产生。在脓毒症免疫抑制阶段，脾脏中的这些浸润中性粒细胞在局部微环境中发生表型变化，表现出中性粒细胞生物标志物如Siglec-F、Ly6G和Siglec-E的高表达。耗竭中性粒细胞或特异性靶向Siglec-F可增强T淋巴细胞功能，并显著改善继发性感染小鼠的存活率。我们确定Siglec-F中性粒细胞是IL-10的主要产生者，其对T淋巴细胞抑制有显著作用，这是一个具有潜在治疗意义的新发现。
