Tissue-resident trained immunity in hepatocytes protects against septic liver injury in zebrafish
Zhuang Wang,
Yuanyuan Liu,
Jing Hu,
Xinwei You,
Jin Yang,
Yuanxing Zhang,
Qin Liu,
Dahai Yang
Affiliations
Zhuang Wang
State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
Yuanyuan Liu
State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
Jing Hu
State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
Xinwei You
State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
Jin Yang
State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China
Yuanxing Zhang
Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai, China
Qin Liu
State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China; Shanghai Engineering Research Center of Maricultured Animal Vaccines, Shanghai 200237, China
Dahai Yang
State Key Laboratory of Bioreactor Engineering, Laboratory for Aquatic Animal Diseases, East China University of Science and Technology, Shanghai 200237, China; Shanghai Engineering Research Center of Maricultured Animal Vaccines, Shanghai 200237, China; Corresponding author
Summary: 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.
