Abstract：
Trained immunity is classically characterized by long-term functional reprogramming of innate immune cells to combat infectious diseases. Infection-induced organ injury is a common clinical severity phenotype of sepsis. However, whether the induction of trained immunity plays a role in protecting septic organ injury remains largely unknown. Here, through establishing an in vivo β-glucan training and lipopolysaccharide (LPS) challenge model in zebrafish larvae, we observe that induction of trained immunity could inhibit pyroptosis of hepatocytes to alleviate septic liver injury, with an elevated trimethyl-histone H3 lysine 4 (H3K4me3) modification that targets mitophagy-related genes. Moreover, we identify a C-type lectin domain receptor in zebrafish, named DrDectin-1, which is revealed as the orchestrator in gating H3K4me3 rewiring-mediated mitophagy activation and alleviating pyroptosis-engaged septic liver injury in vivo. Taken together, our results uncover tissue-resident trained immunity in maintaining liver homeostasis at the whole-animal level and offer an in vivo model to efficiently integrate trained immunity for immunotherapies.
摘要：
经过训练的免疫的典型特征是先天性免疫细胞的长期功能重编程以对抗传染病。感染诱导的器官损伤是脓毒症临床上常见的严重程度表型。然而,训练免疫的诱导是否在保护败血症器官损伤方面起作用仍在很大程度上未知。这里,通过建立斑马鱼幼虫体内β-葡聚糖训练和脂多糖(LPS)攻击模型,我们观察到，诱导训练的免疫可以抑制肝细胞的焦凋亡，减轻脓毒症肝损伤，具有针对线粒体自噬相关基因的三甲基组蛋白H3赖氨酸4（H3K4me3）修饰。此外，我们在斑马鱼中鉴定了一个C型凝集素结构域受体，命名为DrDectin-1，它被揭示为在体内门控H3K4me3重新布线介导的线粒体自噬激活和减轻焦凋亡引起的败血症性肝损伤的协调器。一起来看,我们的结果揭示了组织驻留训练的免疫在整个动物水平上维持肝脏稳态,并提供了一个体内模型,以有效地将训练的免疫整合到免疫疗法中.
