Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses

As one of the most induced genes in activated macrophages, immune-responsive gene 1 ( IRG1 ) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show tha...

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Published inNature cell biology Vol. 24; no. 3; pp. 353 - 363
Main Authors Chen, Lei-Lei, Morcelle, Carmen, Cheng, Zhou-Li, Chen, Xiufei, Xu, Yanping, Gao, Yajing, Song, Junbin, Li, Zhijun, Smith, Matthew D., Shi, Miao, Zhu, Yezhang, Zhou, Neng, Cheng, Meng, He, Chenxi, Liu, Kwei‐Yan, Lu, Guoping, Zhang, Lei, Zhang, Cheng, Zhang, Jinye, Sun, Yiping, Qi, Tuan, Lyu, Yingying, Ren, Zhi-Zhong, Tan, Xian-Ming, Yin, Jiayong, Lan, Fei, Liu, Ying, Yang, Hui, Qian, Maoxiang, Duan, Caiwen, Chang, Xing, Zhou, Yufeng, Shen, Li, Baldwin, Albert S., Guan, Kun-Liang, Xiong, Yue, Ye, Dan
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.03.2022
Nature Publishing Group
Subjects
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13/1
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13/21
13/31
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631/250/262
631/337/176/1988
631/443/319
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Acids
Animals
Anti-inflammatory agents
Biology
Biomedical and Life Sciences
Cancer Research
Catalytic activity
Cell Biology
Deoxyribonucleic acid
Developmental Biology
Dioxygenases - metabolism
DNA
DNA methylation
Drug dosages
Edema
Enzymes
Epigenetics
Gene expression
Genes
Hematology
Inflammation
Itaconic acid
Ketoglutaric acid
Laboratories
Life Sciences
Lipopolysaccharides
Lipopolysaccharides - toxicity
Macrophages
Metabolism
Metabolites
Mice
Mitochondria
Mutation
NF-κB protein
Pathogens
Pediatrics
Signal transduction
Stem Cells
Substrate inhibition
Succinates - metabolism
Succinates - pharmacology
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Summary:As one of the most induced genes in activated macrophages, immune-responsive gene 1 ( IRG1 ) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses. Chen et al. report that the immune modulatory metabolite itaconic acid selectively inhibits the activity of TET DNA dioxygenases to repress the inflammatory responses.
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Current address: Cullgen Inc. Cullgen Inc. 12671 High Bluff Drive, San Diego, CA92130, USA.
Y. X., K-L. G. and D. Y. conceived and supervised the project; L-L. C. designed the experiments and performed most of the experiments with Z-L C. L-L.C. wrote the draft with Y.X and D. Y.; C. M. participated in the initiation the project. A. J. and Q. Z. performed NMR studies using the TET2 protein provided by Z-Z R; C. M., C. Z., J-Y. Z., Y-Y. L, measured the intracellular levels of ITA and other metabolites; X-F. C. and C. M. performed immunofluorescence staining for 5hmC in HEK293T cells and generated constructs overexpressing Irg1 and catalytic defect mutant; J-B. S generated Irg1-KO RAW264.7 cells; M. S., Y-Z. Z. and C. M. performed 5hmC DIP-Seq under the supervision of L. S.; J-Y. Y. performed 5hmC DIP-Seq analysis under the supervision of M-X. Q.; H. Y. and L. Y. performed 5hmC staining; Z-L C. and Z-J. L. quantified genomic 5hmC and 5mC in cells by dot-blot and LC-MS/MS, respectively; C-X. H. performed in vitro assay for KDM activity under the supervision of F. L. (data not shown); Y-J. G., K-Y. L., C.M., G-P. L., and T.Q. conducted LPS administration in mice under the supervision of Y-F. Z. and X. C.; N. Z. performed mouse BMT under the supervision of C-W. D.; Y-P. X. made initial finding of NF-κB and TET2 interaction; A. S. B. participated in the design of NF-κB related experiments; X-M. T. performed statistical analyses.
Author contributions
ISSN:1465-7392
1476-4679
1476-4679
DOI:10.1038/s41556-022-00853-8