Liu Qingxiang, Liu Haitao, Hu Zihan, Zhou Xing, Jin Kai, Huang Yingzi, Huang Wei, Yang Yi
Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People's Republic of China.
School of Life Science, Fudan University, Shanghai, 200000, People's Republic of China.
J Inflamm Res. 2024 May 17;17:3159-3171. doi: 10.2147/JIR.S459706. eCollection 2024.
Sepsis is a life-threatening clinical syndrome caused by dysregulated host response to infection. The mechanism underlying sepsis-induced immune dysfunction remains poorly understood. Natural killer T (NKT) cells are cytotoxic lymphocytes that bridge the innate and adaptive immune systems, the role of NKT cells in sepsis is not entirely understood, and NKT cell cluster differences in sepsis remain unexplored.
Mendelian randomization (MR) analyses were first conducted to investigate the causal relationship between side scatter area (SSC-A) on NKT cells and 28-day mortality of septic patients. A prospective and observational study was conducted to validate the relationship between the percentage of NKT cells and 28-day mortality of sepsis. Then, the single-cell RNA sequencing (scRNA-seq) data of peripheral blood mononuclear cells (PBMCs) from healthy controls and septic patients were profiled.
MR analyses first revealed the protective roles of NKT cells in the 28-day mortality of sepsis. Then, 115 septic patients were enrolled. NKT percentage was significantly higher in survivors (n = 84) compared to non-survivors (n = 31) (%, 5.00 ± 3.46 vs 2.18 ± 1.93, P < 0.0001). Patients with lower levels of NKT cells exhibited a significantly increased risk of 28-day mortality. According to scRNA-seq analysis, NKT cell clusters exhibited multiple distinctive characteristics, including a distinguishing cluster defined as FOSNKT cells, which showed a significant decrease in sepsis. Pseudo-time analysis showed that FOSNKT cells were characterized by upregulated expression of crucial functional genes such as and . CellChat revealed that interactions between FOSNKT cells and adaptive immune cells including B cells and T cells were decreased in sepsis compared to healthy controls.
Our findings indicate that NKT cells may protect against sepsis, and their percentage can predict 28-day mortality. Additionally, we discovered a unique FOSNKT subtype crucial in sepsis immune response, offering novel insights into its immunopathogenesis.
脓毒症是一种由宿主对感染的反应失调引起的危及生命的临床综合征。脓毒症诱导的免疫功能障碍的潜在机制仍知之甚少。自然杀伤T（NKT）细胞是连接固有免疫和适应性免疫系统的细胞毒性淋巴细胞，NKT细胞在脓毒症中的作用尚未完全明确，脓毒症中NKT细胞簇的差异也尚未被探索。
首先进行孟德尔随机化（MR）分析，以研究NKT细胞侧向散射面积（SSC-A）与脓毒症患者28天死亡率之间的因果关系。进行了一项前瞻性观察研究，以验证NKT细胞百分比与脓毒症28天死亡率之间的关系。然后，对来自健康对照和脓毒症患者的外周血单个核细胞（PBMC）的单细胞RNA测序（scRNA-seq）数据进行分析。
MR分析首先揭示了NKT细胞在脓毒症28天死亡率中的保护作用。然后，纳入了115例脓毒症患者。幸存者（n = 84）的NKT百分比显著高于非幸存者（n = 31）（%，5.00±3.46对2.18±1.93，P < 0.0001）。NKT细胞水平较低的患者28天死亡率风险显著增加。根据scRNA-seq分析，NKT细胞簇表现出多个独特特征，包括一个被定义为FOSNKT细胞的独特簇，其在脓毒症中显著减少。伪时间分析表明，FOSNKT细胞的特征是关键功能基因如 和 的表达上调。CellChat显示，与健康对照相比，脓毒症中FOSNKT细胞与包括B细胞和T细胞在内的适应性免疫细胞之间的相互作用减少。
我们的研究结果表明，NKT细胞可能对脓毒症具有保护作用，其百分比可预测28天死亡率。此外，我们发现了一种在脓毒症免疫反应中起关键作用的独特FOSNKT亚型，为其免疫发病机制提供了新的见解。
