中文摘要：
目前，关于全身性感染引发脓毒症中过度炎症反应和免疫功能障碍的机制尚不清楚。细胞外组蛋白会加剧脓毒症病理进程，但其来源和作用机制仍不明确。本研究揭示，中性粒细胞来源的髓过氧化物酶通过抑制组蛋白释放，在调控脾巨噬细胞捕获的真菌和细菌过程中发挥脓毒症缓解作用。在系统性念珠菌感染中，吞噬受体SIGNR1介导的微生物捕获通过促进边缘区浸润和T细胞死亡依赖性组蛋白释放，中和了髓过氧化物酶活性。组蛋白和菌丝可诱导邻近CD169+巨噬细胞产生细胞因子（包括G-CSF），这些因子通过缩短成熟Ly6G高表达中性粒细胞的存活时间，选择性耗竭该类细胞，转而促进具有氧化爆发缺陷的未成熟Ly6G低表达中性粒细胞存活。在脓毒症患者血浆中，这些介质可缩短成熟中性粒细胞寿命，并与中性粒细胞死亡标志物相关。因此，高G-CSF水平和中性粒细胞寿命缩短活性与脓毒症患者死亡率密切相关。综上，病原体通过利用吞噬受体，借助下游效应因子对中性粒细胞寿命的有害影响，削弱了先天性和适应性免疫功能。
英文摘要：
The mechanisms linking systemic infection to hyperinflammation and immune dysfunction in sepsis are poorly understood. Extracellular histones promote sepsis pathology, but their source and mechanism of action remain unclear. Here, we show that by controlling fungi and bacteria captured by splenic macrophages, neutrophil-derived myeloperoxidase attenuates sepsis by suppressing histone release. In systemic candidiasis, microbial capture via the phagocytic receptor SIGNR1 neutralizes myeloperoxidase by facilitating marginal zone infiltration and T cell death-dependent histone release. Histones and hyphae induce cytokines in adjacent CD169 macrophages including G-CSF that selectively depletes mature Ly6Ghigh neutrophils by shortening their lifespan in favour of immature Ly6Glow neutrophils with a defective oxidative burst. In sepsis patient plasma, these mediators shorten mature neutrophil lifespan and correlate with neutrophil mortality markers. Consequently, high G-CSF levels and neutrophil lifespan shortening activity are associated with sepsis patient mortality. Hence, by exploiting phagocytic receptors, pathogens degrade innate and adaptive immunity through the detrimental impact of downstream effectors on neutrophil lifespan.
论文信息：
论文题目：
Microbe capture by splenic macrophages triggers sepsis via T cell-death-dependent neutrophil lifespan shortening
期刊名称：Nature Communications
时间期卷：13, Article number: 4658 (2022)
在线时间：2022年8月9日
DOI：doi.org/10.1038/s41467-022-32320-1
产品信息：
货号：CP-005-005
规格：5ml+5ml
品牌：Liposoma
产地：荷兰
名称：Clodronate Liposomes and Control Liposomes
办事处：Target Technology（靶点科技）
氯膦酸盐脂质体清除脾脏巨噬细胞在脓毒血症模型中心粒细胞功能研究，荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于Nature Communications：
氯膦酸二钠脂质体清除巨噬细胞助力脾脏脓毒症模型免疫研究
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：
Mice were injected intravenously with 1 mg of Clo-L or PBS-L (Liposoma) and the subsequent day intraperitoneally with 2.5 μg rG-CSF (BioLegend) or vehicle (PBS). Analysis of neutrophil populations was performed 2 days after rG-CSF injection, according to the methods described in flow cytometric analysis.
Neutrophil depletion was achieved with intraperitoneal injection of 150 μg anti-Ly6G Ab (BioXCell) or IgG isotype control (BioXCell) at day −1 and day 0 (day of infection). Macrophage depletion was performed with intravenous administration of 1 mg Clodronate liposomes (Clo-L) or 1 mg PBS liposomes (PBS-L) as control (Liposoma) at 1 day prior to infection.
