Akama Yuichi, Murao Atsushi, Aziz Monowar, Wang Ping
Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY 11030, United States.
Departments of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, 500 Hofstra Blvd, Hempstead, NY 11549, United States.
J Leukoc Biol. 2025 May 7;117(5). doi: 10.1093/jleuko/qiaf063.
Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. Neutrophils act as first line of defense against infection, but their function can become impaired in sepsis. CD300 antigen-like family member d (CD300ld), predominantly expressed on neutrophils, associates with Fc receptor common gamma-chain (FcRγ chain), a component vital for phagocytosis. In this study, we investigated the role of CD300ld in neutrophil phagocytosis. Our results demonstrate a marked decrease in CD300ld expression on neutrophils isolated from both septic mice and patients. CD300ld was positively correlated with bacterial phagocytosis in neutrophils. The transcriptomic analysis of CD300ld knock-out neutrophils revealed a downregulation of genes related to defense response to bacteria, suggesting that CD300ld is a key modulator of bacterial clearance. Stimulation of CD300ld with an agonist antibody in neutrophils led to the activation of Rac2, a key regulator of actin polymerization, facilitating the enhanced phagocytosis. Furthermore, CD300ld activation significantly enhanced the in vitro phagocytosis of Escherichia coli and Staphylococcus aureus by neutrophils. Septic mice adoptively transferred with CD300ld-activated neutrophils exhibited markedly reduced bacterial loads in the blood and peritoneum, decreased inflammatory cytokine levels, and alleviated organ injury. These findings highlight the critical role of CD300ld signaling in neutrophil-mediated bacterial clearance in sepsis and provide a solid foundation for future research aimed at developing novel immunotherapies against this deadly disease condition.
脓毒症是一种由对感染的免疫反应失调引起的危及生命的病症。中性粒细胞作为抵御感染的第一道防线，但其功能在脓毒症中可能会受损。CD300抗原样家族成员d（CD300ld）主要在中性粒细胞上表达，与吞噬作用至关重要的组成部分Fc受体共同γ链（FcRγ链）相关联。在本研究中，我们调查了CD300ld在中性粒细胞吞噬作用中的作用。我们的结果表明，从脓毒症小鼠和患者中分离出的中性粒细胞上CD300ld的表达显著降低。CD300ld与中性粒细胞中的细菌吞噬作用呈正相关。对CD300ld基因敲除的中性粒细胞进行转录组分析发现，与细菌防御反应相关的基因下调，这表明CD300ld是细菌清除的关键调节因子。用激动剂抗体刺激中性粒细胞中的CD300ld会导致Rac2激活，Rac2是肌动蛋白聚合的关键调节因子，促进吞噬作用增强。此外，CD300ld激活显著增强了中性粒细胞对大肠杆菌和金黄色葡萄球菌的体外吞噬作用。接受CD300ld激活的中性粒细胞过继转移的脓毒症小鼠，其血液和腹膜中的细菌载量显著降低，炎症细胞因子水平降低，器官损伤减轻。这些发现突出了CD300ld信号在脓毒症中中性粒细胞介导的细菌清除中的关键作用，并为未来旨在开发针对这种致命疾病状况的新型免疫疗法的研究提供了坚实的基础。
