Targeted macrophage phagocytosis by Irg1/itaconate axis improves the prognosis of intracerebral hemorrhagic stroke and peritonitisResearch in context
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,
Jian-Nan Zhang,
Yamei Wang,
Yabin Lu,
Liyong Wang,
Chenguang Zhang,
Peipei Wang,
Jing An,
Fei Yang,
Qian Li
Affiliations
Zhaoli Luo
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Ziyang Sheng
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Liye Hu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Lei Shi
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yichen Tian
School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Xiaochu Zhao
School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Wei Yang
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Zhongnan Xiao
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Danmin Shen
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Weihua Wu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Ting Lan
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Boqian Zhao
School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Xiaogang Wang
School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Nan Zhuang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Jian-Nan Zhang
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yamei Wang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Yabin Lu
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Liyong Wang
Core Facilities for Molecular Biology, Capital Medical University, Beijing 100069, China
Chenguang Zhang
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Peipei Wang
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Jing An
Department of Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
Fei Yang
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing 100069, China; Corresponding author.
Qian Li
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China; Laboratory for Clinical Medicine, Beijing Key Laboratory of Neural Regeneration and Repair, Capital Medical University, Beijing 100069, China; Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Capital Medical University, Beijing 100069, China; Corresponding author.
Summary: 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 (Irg1flox/flox; Cx3cr1creERT/+, 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 (Keap1), consequent in nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and transcriptional activation of Cd36 gene. Blocking the function of CD36 completely abolished the phagocytosis-promoting effects of Irg1/itaconate axis in vitro and in vivo. Interpretation: Our findings provide a potential therapeutic target for phagocytosis-deficiency disorders, supporting further development towards clinical application for the benefit of stroke and peritonitis patients. Funding: The National Natural Science Foundation of China (32070735, 82371321 to Q. Li, 82271240 to F. Yang) and the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ202010025033 to Q. Li).
