Abstract
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.
Keywords:
Immunology; Inflammation; Innate immunity; Monocytes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Candida albicans
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Candidiasis / genetics
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Candidiasis / immunology
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Epigenesis, Genetic / genetics*
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Epigenesis, Genetic / immunology
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Fumarates / metabolism
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Glycolysis / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Immunity, Innate / genetics*
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Immunity, Innate / immunology
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Immunologic Memory / genetics*
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Immunologic Memory / immunology
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Interleukin-1beta / metabolism
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Interleukin-6 / metabolism
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Isocitrate Dehydrogenase / metabolism*
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Ketoglutaric Acids / metabolism
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Lipopolysaccharides / pharmacology
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Metabolic Networks and Pathways / genetics*
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Metabolic Networks and Pathways / immunology
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Mice
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Mice, Knockout
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Monocytes / drug effects
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Monocytes / metabolism*
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Retinitis Pigmentosa / genetics
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Retinitis Pigmentosa / metabolism
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Succinic Acid / metabolism
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Tumor Necrosis Factor-alpha / metabolism
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beta-Glucans / immunology
Substances
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Fumarates
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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IL1B protein, mouse
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Interleukin-1beta
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Interleukin-6
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Ketoglutaric Acids
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Lipopolysaccharides
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MIRN9 microRNA, mouse
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MicroRNAs
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Tnf protein, mouse
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Tumor Necrosis Factor-alpha
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beta-Glucans
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interleukin-6, mouse
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Succinic Acid
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Isocitrate Dehydrogenase
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isocitrate dehydrogenase 3, mouse
Grants and funding
This work was supported by National Science and Technology Major Project 2018ZX10302302-002 and 2018ZX10731301-004, National Natural Science Foundation of China Grant 31600747; the youth innovation talents program of the education department of Guangdong province through University Innovation Strong School Project Grants 2016KQNCX141 and Q17024049; Guangzhou Science and Technology Innovation Committee Grant 201804010317; Guangzhou Municipal Science and Technology Project (No. 201904010067); Natural Science Foundation of Guangdong Province (No. 2018A030313560,2020A1515010009).