Translational Medicine Research Center, Medical Innovation Research Division and the Fourth Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
Department of Burn Surgery, the First Affiliated Hospital of Naval Medical University, Shanghai, 200433, China.
Mil Med Res. 2023 Jun 19;10(1):27. doi: 10.1186/s40779-023-00462-y.
Sustained yet intractable immunosuppression is commonly observed in septic patients, resulting in aggravated clinical outcomes. However, due to the substantial heterogeneity within septic patients, precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.
We adopted cross-species, single-cell RNA sequencing (scRNA-seq) analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis. Flow cytometry, laser scanning confocal microscopy (LSCM) imaging and Western blotting were applied to identify the presence of S100A9 monocytes at protein level. To interrogate the immunosuppressive function of this subset, splenic monocytes isolated from septic wild-type or S100a9 mice were co-cultured with naïve CD4 T cells, followed by proliferative assay. Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.
ScRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis, for which distinct monocyte subsets were enriched in disparate subclusters of septic patients. We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR (HLA-DR), which were prominently enriched in septic patients and might exert immunosuppressive function. By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments, we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice, corresponding to HLA-DRS100A monocytes in human sepsis. Moreover, we found that S100A9 monocytes exhibited profound immunosuppressive function on CD4 T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.
This study identifies HLA-DRS100A monocytes correlated with immunosuppressive state upon septic challenge, inhibition of which can markedly mitigate sepsis-induced immune depression, thereby providing a novel therapeutic strategy for the management of sepsis.
脓毒症患者常出现持续且难以控制的免疫抑制，导致临床结局恶化。然而，由于脓毒症患者存在较大的异质性，因此仍然缺乏精确的指标来解析脓毒症患者的临床轨迹和免疫变化。
我们采用了跨物种单细胞 RNA 测序(scRNA-seq)分析，该分析基于包含脓毒症患者循环免疫细胞谱和脓毒症小鼠模型免疫细胞图谱的两个已发表数据集。应用流式细胞术、激光共聚焦显微镜(LSCM)成像和 Western blot 来鉴定 S100A9 单核细胞在蛋白质水平上的存在。为了探究这个亚群的免疫抑制功能，从脓毒症野生型或 S100a9 小鼠中分离出脾脏单核细胞，并与幼稚 CD4 T 细胞共培养，然后进行增殖测定。通过口服给予帕奎莫德来抑制 S100A9。
对人类脓毒症的 scRNA-seq 分析显示，脓毒症发病后单核细胞区室存在明显的异质性，不同的单核细胞亚群在不同的脓毒症患者亚群中富集。我们鉴定出一种独特的单核细胞亚群，其特征是 S100 家族基因高表达，人类白细胞抗原 DR(HLA-DR)低表达，该亚群在脓毒症患者中明显富集，并可能发挥免疫抑制功能。通过将脓毒症小鼠模型的单细胞转录组学与体内实验相结合，我们发现了一种类似的单核细胞亚群，该亚群与晚期脓毒症和脓毒症小鼠的免疫功能受损状态显著相关，与人类脓毒症中的 HLA-DRS100A 单核细胞相对应。此外，我们发现 S100A9 单核细胞对 CD4 T 细胞免疫反应具有显著的免疫抑制作用，使用帕奎莫德阻断 S100A9 可部分逆转脓毒症引起的免疫抑制。
本研究鉴定出与脓毒症挑战后免疫抑制状态相关的 HLA-DRS100A 单核细胞，抑制其功能可显著减轻脓毒症引起的免疫抑制，从而为脓毒症的治疗提供了一种新的治疗策略。
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