Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity
Trained monocytes and macrophages produce reactive oxygen species (ROS), which trigger antioxidative glutathione (GSH) response to buffer the rising ROS. However, whether and how the trained immunity is shaped by GSH synthesis remains unknown. Here, we report that β-glucan-trained macrophages from m...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-12-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231721003669 |
| _version_ | 1819174584679661568 |
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| author | Haibo Su Jiaxin Huang Shufeng Weng Baoying Zhang Tianran Zhang Ying Xu |
| author_facet | Haibo Su Jiaxin Huang Shufeng Weng Baoying Zhang Tianran Zhang Ying Xu |
| author_sort | Haibo Su |
| collection | DOAJ |
| description | Trained monocytes and macrophages produce reactive oxygen species (ROS), which trigger antioxidative glutathione (GSH) response to buffer the rising ROS. However, whether and how the trained immunity is shaped by GSH synthesis remains unknown. Here, we report that β-glucan-trained macrophages from mice harboring a myeloid-specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) showed impaired GSH synthesis and decreased proinflammatory cytokine production in response to lipopolysaccharide challenge. Gclc deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of c-Myc transcription factors, abrogating the energy utilization and the metabolic reprogramming that allows β-glucan-trained macrophages to switch to glycolysis and glutaminolysis. Furthermore, Gclc deletion repressed effective H3K27me3 demethylation in the promoters of immunometabolic genes, such as Gls, Hk2, and Glut1, in β-glucan-trained macrophages by promoting the methyltransferase enhancer of zeste homolog 2 (EZH2). In vivo, myeloid-specific ablation of Gclc decreased the secretion of proinflammatory cytokines upon rechallenge with Candida albicans and these animals were less protected against the infection, compared with control littermates. Moreover, pharmacological inhibition of EZH2 enhanced the trained immunity response against Candida infection in Gclc-deficient mouse and human peripheral blood mononuclear cells treated with GCLC inhibitor buthionine sulfoximine (BSO). Thus, antioxidative GSH synthesis supports an environment conducive to β-glucan-induced metabolic and epigenetic reprogramming in trained immunity, allowing exploration of its functional consequences in autoimmune or inflammatory disease. |
| first_indexed | 2024-12-22T20:41:18Z |
| format | Article |
| id | doaj.art-d4f0c22794b444b99bf47fd04ac90edf |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-22T20:41:18Z |
| publishDate | 2021-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-d4f0c22794b444b99bf47fd04ac90edf2022-12-21T18:13:20ZengElsevierRedox Biology2213-23172021-12-0148102206Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunityHaibo Su0Jiaxin Huang1Shufeng Weng2Baoying Zhang3Tianran Zhang4Ying Xu5GMU-GIBH Joint School of Life Science, Guangzhou Medical University, No. 195 Dongfengxi Road, Guangzhou, 510000, China; Corresponding author.GMU-GIBH Joint School of Life Science, Guangzhou Medical University, No. 195 Dongfengxi Road, Guangzhou, 510000, ChinaState Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, No. 220 Handan Road, Shanghai, 200433, ChinaGMU-GIBH Joint School of Life Science, Guangzhou Medical University, No. 195 Dongfengxi Road, Guangzhou, 510000, ChinaState Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, No. 220 Handan Road, Shanghai, 200433, ChinaState Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, No. 220 Handan Road, Shanghai, 200433, China; Corresponding author.Trained monocytes and macrophages produce reactive oxygen species (ROS), which trigger antioxidative glutathione (GSH) response to buffer the rising ROS. However, whether and how the trained immunity is shaped by GSH synthesis remains unknown. Here, we report that β-glucan-trained macrophages from mice harboring a myeloid-specific deletion of the catalytic subunit of glutamate-cysteine ligase (Gclc) showed impaired GSH synthesis and decreased proinflammatory cytokine production in response to lipopolysaccharide challenge. Gclc deficiency compromised the activation of mammalian target of rapamycin-1 (mTOR) and expression of c-Myc transcription factors, abrogating the energy utilization and the metabolic reprogramming that allows β-glucan-trained macrophages to switch to glycolysis and glutaminolysis. Furthermore, Gclc deletion repressed effective H3K27me3 demethylation in the promoters of immunometabolic genes, such as Gls, Hk2, and Glut1, in β-glucan-trained macrophages by promoting the methyltransferase enhancer of zeste homolog 2 (EZH2). In vivo, myeloid-specific ablation of Gclc decreased the secretion of proinflammatory cytokines upon rechallenge with Candida albicans and these animals were less protected against the infection, compared with control littermates. Moreover, pharmacological inhibition of EZH2 enhanced the trained immunity response against Candida infection in Gclc-deficient mouse and human peripheral blood mononuclear cells treated with GCLC inhibitor buthionine sulfoximine (BSO). Thus, antioxidative GSH synthesis supports an environment conducive to β-glucan-induced metabolic and epigenetic reprogramming in trained immunity, allowing exploration of its functional consequences in autoimmune or inflammatory disease.http://www.sciencedirect.com/science/article/pii/S2213231721003669Trained immunityInnate immune memoryCatalytic subunit of glutamate-cysteine ligaseROSGSH |
| spellingShingle | Haibo Su Jiaxin Huang Shufeng Weng Baoying Zhang Tianran Zhang Ying Xu Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity Redox Biology Trained immunity Innate immune memory Catalytic subunit of glutamate-cysteine ligase ROS GSH |
| title | Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity |
| title_full | Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity |
| title_fullStr | Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity |
| title_full_unstemmed | Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity |
| title_short | Glutathione synthesis primes monocytes metabolic and epigenetic pathway for β-glucan-trained immunity |
| title_sort | glutathione synthesis primes monocytes metabolic and epigenetic pathway for β glucan trained immunity |
| topic | Trained immunity Innate immune memory Catalytic subunit of glutamate-cysteine ligase ROS GSH |
| url | http://www.sciencedirect.com/science/article/pii/S2213231721003669 |
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