Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China.
Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China; Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing 100038, China.
Cell Rep. 2023 Sep 26;42(9):113044. doi: 10.1016/j.celrep.2023.113044. Epub 2023 Aug 28.
Secondary infection in patients with sepsis triggers a new wave of inflammatory response, which aggravates organ injury and increases mortality. Trained immunity boosts a potent and nonspecific response to the secondary challenge and has been considered beneficial for the host. Here, using a murine model of polymicrobial infection, we find that the primary infection reprograms granulocytes to boost enhanced inflammatory responses to the secondary infection, including the excessive production of inflammatory cytokines, respiratory burst, and augmented phagocytosis capacity. However, these reprogramed granulocytes exhibit "non-classic" characteristics of innate immune memory. Two mechanisms are independently involved in the innate immune memory of granulocytes: a metabolic shift in favor of glycolysis and fatty acid synthesis and chromatin remodeling leading to the transcriptional inactivity of genes encoding inhibitors of TLR4-initiated signaling pathways. Counteracting the deleterious effects of stressed granulocytes on anti-infection immunity might provide a strategy to fight secondary infections during sepsis.
脓毒症患者的继发感染会引发新一轮炎症反应，从而加重器官损伤并增加死亡率。训练有素的免疫会增强对继发挑战的有效且非特异性反应，被认为对宿主有益。在这里，我们使用多微生物感染的小鼠模型发现，原发性感染会使粒细胞重新编程，以增强对二次感染的炎症反应，包括过度产生炎症细胞因子、呼吸爆发和增强吞噬能力。然而，这些重新编程的粒细胞表现出先天免疫记忆的“非经典”特征。粒细胞的先天免疫记忆涉及两种独立的机制：有利于糖酵解和脂肪酸合成的代谢转变，以及导致编码 TLR4 起始信号通路抑制剂的基因转录失活的染色质重塑。对抗应激粒细胞对抗感染免疫的有害影响可能为脓毒症期间对抗继发感染提供一种策略。
