miR-9-5p regulates immunometabolic and epigenetic pathways in β-glucan-trained immunity via IDH3α

• Published in: JCI insight Vol. 6; no. 9
• Main Authors: Su, Haibo, Liang, Zhongping, Weng, ShuFeng, Sun, Chaonan, Huang, Jiaxin, Zhang, TianRan, Wang, Xialian, Wu, Shanshan, Zhang, Zhi, Zhang, Yiqi, Gong, Qing, Xu, Ying
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 10.05.2021; American Society for Clinical investigation
• Subjects: Animals; beta-Glucans - immunology; Candida albicans; Candidiasis - genetics; Candidiasis - immunology; Epigenesis, Genetic - genetics; Epigenesis, Genetic - immunology; Fumarates - metabolism; Glycolysis - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunity, Innate - genetics; Immunity, Innate - immunology; Immunologic Memory - genetics; Immunologic Memory - immunology; Immunology; Inflammation; Interleukin-1beta - metabolism; Interleukin-6 - metabolism; Isocitrate Dehydrogenase - metabolism; Ketoglutaric Acids - metabolism; Lipopolysaccharides - pharmacology; Metabolic Networks and Pathways - genetics; Metabolic Networks and Pathways - immunology; Mice; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Monocytes - drug effects; Monocytes - metabolism; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - metabolism; Succinic Acid - metabolism; Tumor Necrosis Factor-alpha - metabolism; Innate immunity; Monocytes; Inflammation; Immunology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.144260

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.