Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis

Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection. The present data deposit includes processed and quality-controlled data tables for: 1. Whole blood leukocytes profiled with the BD Rhapsody platform in a cohort of 39 sepsis patients (RNA and protein count matrices, as well as their accompanying metadata table) 2. Circulating HSCs in blood profiled with the 10X multiomics platform in a cohort of 27 sepsis patients (RNA and ATAC-seq count matrices, as well as their accompanying metadata tables) IMPORTANT NOTE: The files in Version 1.0 are incomplete (missing the cell barcode list and gene/feature names).Please download Version 1.1 for the complete package (includes barcode and feature list files aligned to the matrices).脓毒症是感染后宿主出现失调的炎症反应所引发的一类尚未完全阐明的病理过程，可导致危及生命的器官功能障碍。本研究证实，中性粒细胞（neutrophils）与紧急粒细胞生成（emergency granulopoiesis）在脓毒症进程中驱动了适应不良的免疫反应。我们构建了脓毒症免疫反应的全血单细胞多组学图谱（共计272993个细胞，纳入39名受试者），鉴定出了免疫抑制性成熟及未成熟中性粒细胞亚群。共培养实验显示，CD66b+脓毒症中性粒细胞可抑制CD4+ T细胞的增殖与活化。对循环造血干祖细胞（hematopoietic stem and progenitor cells，HSPCs）的单细胞多组学分析（共计29366个细胞，纳入27名受试者）表明，脓毒症患者的粒细胞生成过程发生异常改变。上述特征在预后不良的患者亚群中显著富集，同时伴随特定的脓毒症反应特征：包括IL1R2+未成熟中性粒细胞比例升高、造血干祖细胞中紧急粒细胞生成的表观遗传与转录组特征，以及跨不同感染病因和综合征的STAT3介导的基因调控网络。本研究结果为重症感染的分层医疗提供了潜在的治疗靶点与应用契机。 本数据集包含经过预处理与质量控制的数据表格，具体涵盖： 1. 采用BD Rhapsody平台完成测序的39名脓毒症患者全血白细胞转录组与蛋白组数据（包含RNA及蛋白计数矩阵，以及配套的元数据表） 2. 采用10X多组学平台完成测序的27名脓毒症患者循环造血干细胞数据（包含RNA及ATAC-seq计数矩阵，以及配套的元数据表） 重要提示：1.0版本的文件存在缺失，缺少细胞条形码列表与基因/特征名称文件。请下载1.1版本以获取完整数据包（包含与计数矩阵对齐的条形码及特征列表文件）。