Department of Hematology, Fujian Provincial Key Laboratory of Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
Department of Emergency Intensive Care Unit, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou 350001, Fujian, China.
J Leukoc Biol. 2023 Oct 26;114(5):443-458. doi: 10.1093/jleuko/qiad088.
This study tested the hypothesis that recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances polymorphonuclear neutrophils (PMNs) via interleukin (IL)-1β to improve the prognosis of secondary infection in sepsis. The latter stage of sepsis is prone to induce immunosuppression, resulting in secondary fatal infections. Recombinant GM-CSF has become a way for sepsis-induced immunosuppression due to its immunomodulatory effect. However, the functional impact of GM-CSF on PMNs in sepsis remains obscure. This study aimed to study the role of recombinant GM-CSF on the bactericidal ability of PMNs in septic mice, assessing its effect on the prognosis of secondary pneumonia, and explore the mechanism of recombinant GM-CSF by intervening PMNs in patients with sepsis. The C57BL/6J sepsis mouse model was induced by cecal ligation and puncture. Recombinant murine GM-CSF (rmGM-CSF) was used in vivo when mice developed immunosuppression, which was characterized by abnormal bactericidal function of PMNs in peripheral blood. rmGM-CSF improved the prognosis of secondary pneumonia and reversed the function of PMNs. PMNs isolated by Percoll from septic patients were treated by recombinant human GM-CSF (rhGM-CSF) in vitro. The expression of CD11b, reactive oxygen species, phagocytosis, and neutrophil extracellular trap release in PMNs were enhanced by rhGM-CSF treatments. Whole-transcriptomic sequencing of mouse PMNs indicated that recombinant GM-CSF increased the expression of Il1b gene in PMNs. Blocking and inhibiting IL-1β release effectively counteracted the enhancing effect of GM-CSF on the bactericidal function of PMNs. rmGM-CSF enhances the bactericidal function of PMNs in vivo and improves the prognosis of secondary pneumonia in septic mice, and recombinant GM-CSF increases IL-1β precursor reserves, which, if stimulated, can rapidly enhance the bactericidal capacity of PMNs.
这项研究检验了这样一个假设，即重组粒细胞-巨噬细胞集落刺激因子（GM-CSF）通过白细胞介素（IL）-1β增强多形核粒细胞（PMN），从而改善脓毒症继发感染的预后。脓毒症的后期阶段容易引发免疫抑制，导致继发致命感染。由于具有免疫调节作用，重组 GM-CSF 已成为治疗脓毒症引起的免疫抑制的一种方法。然而，GM-CSF 对脓毒症中 PMN 的功能影响仍不清楚。本研究旨在研究重组 GM-CSF 对脓毒症小鼠 PMN 杀菌能力的作用，评估其对继发性肺炎预后的影响，并通过干预脓毒症患者的 PMN 来探索重组 GM-CSF 的作用机制。采用盲肠结扎穿孔法建立 C57BL/6J 脓毒症小鼠模型。当小鼠出现免疫抑制时（表现为外周血 PMN 杀菌功能异常），用重组鼠 GM-CSF（rmGM-CSF）进行体内治疗。rmGM-CSF 改善了继发性肺炎的预后，并逆转了 PMN 的功能。从脓毒症患者中用 Percoll 分离 PMN，在体外用重组人 GM-CSF（rhGM-CSF）进行处理。rhGM-CSF 增强了 PMN 中 CD11b、活性氧、吞噬作用和中性粒细胞胞外陷阱释放的表达。对小鼠 PMN 的全转录组测序表明，重组 GM-CSF 增加了 PMN 中 Il1b 基因的表达。阻断和抑制 IL-1β释放可有效拮抗 GM-CSF 对 PMN 杀菌功能的增强作用。rmGM-CSF 增强了脓毒症小鼠体内 PMN 的杀菌功能，并改善了继发性肺炎的预后，重组 GM-CSF 增加了 IL-1β前体储备，如果受到刺激，可迅速增强 PMN 的杀菌能力。
