Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitis

作者：Zhaoli Luo, Ziyang Sheng, Liye Hu, Lei Shi, Yichen Tian, Xiaochu Zhao, Wei Yang, Zhongnan Xiao, Danmin Shen, Weihua Wu, Ting Lan, Boqian Zhao, Xiaogang Wang, Nan Zhuang, Jiannan Zhang, Yamei Wang, Yabin Lü, Liyong Wang, Chenguang Zhang, Peipei Wang, Jing An, Fei Yang, Qian Li · 发表于：EBioMedicine · 年份：2024 · DOI：10.1016/j.ebiom.2024.104993 · 被引用次数：56 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer、Gut microbiota and health

Background Macrophages are innate immune cells whose phagocytosis function is critical to the prognosis of stroke and peritonitis. cis -aconitic decarboxylase immune-responsive gene 1 (Irg1) and its metabolic product itaconate inhibit bacterial infection, intracellular viral replication, and inflammation in macrophages. Here we explore whether itaconate regulates phagocytosis. Methods Phagocytosis of macrophages was investigated by time-lapse video recording, flow cytometry, and immunofluorescence staining in macrophage/microglia cultures isolated from mouse tissue. Unbiased RNA-sequencing and ChIP-sequencing assays were used to explore the underlying mechanisms. The effects of Irg1/itaconate axis on the prognosis of intracerebral hemorrhagic stroke (ICH) and peritonitis was observed in transgenic ( Irg1 flox/flox ; Cx3cr1 creERT/+ , cKO) mice or control mice in vivo . Findings In a mouse model of ICH, depletion of Irg1 in macrophage/microglia decreased its phagocytosis of erythrocytes, thereby exacerbating outcomes (n = 10 animals/group, p < 0.05). Administration of sodium itaconate/4-octyl itaconate (4-OI) promoted macrophage phagocytosis (n = 7 animals/group, p < 0.05). In addition, in a mouse model of peritonitis, Irg1 deficiency in macrophages also inhibited phagocytosis of Staphylococcus aureus (n = 5 animals/group, p < 0.05) and aggravated outcomes (n = 9 animals/group, p < 0.05). Mechanistically, 4-OI alkylated cysteine 155 on the Kelch-like ECH-associated protein 1 (...