miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α
Trained immunity, induced by β-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway med...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-05-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.144260 |
| _version_ | 1818723227531214848 |
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| author | Haibo Su Zhongping Liang ShuFeng Weng Chaonan Sun Jiaxin Huang TianRan Zhang Xialian Wang Shanshan Wu Zhi Zhang Yiqi Zhang Qing Gong Ying Xu |
| author_facet | Haibo Su Zhongping Liang ShuFeng Weng Chaonan Sun Jiaxin Huang TianRan Zhang Xialian Wang Shanshan Wu Zhi Zhang Yiqi Zhang Qing Gong Ying Xu |
| author_sort | Haibo Su |
| collection | DOAJ |
| description | Trained immunity, induced by β-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR–9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that β-glucan–trained miR–9-5p–/– monocytes showed decreased IL-1β, IL-6, and TNF-α production after LPS stimulation. Trained miR–9-5p–/– mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR–9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR–9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. β-Glucan–trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR–9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity. |
| first_indexed | 2024-12-17T21:07:10Z |
| format | Article |
| id | doaj.art-50bbd7e7e63b49e3a2e046a36ef51027 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-17T21:07:10Z |
| publishDate | 2021-05-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-50bbd7e7e63b49e3a2e046a36ef510272022-12-21T21:32:33ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-05-0169miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3αHaibo SuZhongping LiangShuFeng WengChaonan SunJiaxin HuangTianRan ZhangXialian WangShanshan WuZhi ZhangYiqi ZhangQing GongYing XuTrained immunity, induced by β-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR–9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that β-glucan–trained miR–9-5p–/– monocytes showed decreased IL-1β, IL-6, and TNF-α production after LPS stimulation. Trained miR–9-5p–/– mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR–9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR–9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. β-Glucan–trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR–9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity.https://doi.org/10.1172/jci.insight.144260ImmunologyInflammation |
| spellingShingle | Haibo Su Zhongping Liang ShuFeng Weng Chaonan Sun Jiaxin Huang TianRan Zhang Xialian Wang Shanshan Wu Zhi Zhang Yiqi Zhang Qing Gong Ying Xu miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α JCI Insight Immunology Inflammation |
| title | miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α |
| title_full | miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α |
| title_fullStr | miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α |
| title_full_unstemmed | miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α |
| title_short | miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α |
| title_sort | mir 9 5p regulates immunometabolic and epigenetic pathways in β glucan trained immunity via idh3α |
| topic | Immunology Inflammation |
| url | https://doi.org/10.1172/jci.insight.144260 |
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