Mu Di, Yang Jin, Jiang Yu, Wang Zhuang, Chen Weijie, Huang Jianchang, Zhang Yuanxing, Liu Qin, Yang Dahai
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China.
Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China.
J Immunol. 2022 Aug 15;209(4):783-795. doi: 10.4049/jimmunol.2200225. Epub 2022 Jul 27.
Trained immunity defines long-term memory of innate immunity based on transcriptional, epigenetic, and metabolic modifications of myeloid cells, which are characterized by elevated proinflammatory responses toward homologous or heterologous secondary stimuli in mammals. However, the evidence of trained immunity-associated immune cells and its molecular mechanism in teleost fish remains largely unknown. In this study, we established a trained immunity activation model in turbot () and found that administration with β-glucan induces protection against a bacterial infection. Through single-cell RNA sequencing to annotate 14 clusters of innate and adaptive immune cells, as well as two clusters of blood cells, from head kidney and spleen, respectively, we characterized that neutrophil displays cardinal features of trained immunity by analyzing the expression abundance of trained immunity database-related genes at the single-cell level. Subsequently, through establishing an in vivo training and in vitro neutrophil challenge model, we found that the trained neutrophils exhibit a significant elevation of the IL-1R signaling pathway after infection. Furthermore, inhibition of neutrophil's IL-1R signaling pathway through anakinra treatment impaired the heightened production of reactive oxygen, nitrogen species, lactate, as well as the neutrophil extracellular traps formation and bacterial killing ability. Taken together, these findings characterized neutrophil as the orchestrator to express features of trained immunity, and revealed that the IL-1R signaling pathway plays a critical role in induction of trained immunity for bacterial clearance in teleost fish.
训练有素的免疫基于髓细胞的转录、表观遗传和代谢修饰来定义先天免疫的长期记忆，其特征是在哺乳动物中对同源或异源二次刺激的促炎反应增强。然而，硬骨鱼中与训练有素的免疫相关的免疫细胞及其分子机制的证据仍然 largely 未知。在本研究中，我们在大菱鲆（）中建立了一个训练有素的免疫激活模型，并发现用β-葡聚糖给药可诱导对细菌感染的保护作用。通过单细胞RNA测序分别注释来自头肾和脾脏的14个先天和适应性免疫细胞簇以及两个血细胞簇，我们通过在单细胞水平分析训练有素的免疫数据库相关基因的表达丰度，表征中性粒细胞具有训练有素的免疫的主要特征。随后，通过建立体内训练和体外中性粒细胞攻击模型，我们发现训练后的中性粒细胞在感染后IL-1R信号通路显著升高。此外，通过阿那白滞素治疗抑制中性粒细胞的IL-1R信号通路损害了活性氧、氮物种、乳酸的升高产生，以及中性粒细胞胞外陷阱的形成和细菌杀伤能力。综上所述，这些发现将中性粒细胞表征为表达训练有素的免疫特征的协调者，并揭示IL-1R信号通路在硬骨鱼中诱导训练有素的免疫以清除细菌方面起关键作用。
