miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α
Haibo Su, … , Qing Gong, Ying Xu
Haibo Su, … , Qing Gong, Ying Xu
Published May 10, 2021
Citation Information: JCI Insight. 2021;6(9):e144260. https://doi.org/10.1172/jci.insight.144260.
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Research Article Immunology Inflammation

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

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.

Authors

Haibo Su, Zhongping Liang, ShuFeng Weng, Chaonan Sun, Jiaxin Huang, TianRan Zhang, Xialian Wang, Shanshan Wu, Zhi Zhang, Yiqi Zhang, Qing Gong, Ying Xu

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Figure 1

miR–9-5p induction is dependent on the Dectin-1/Akt/mTOR/GSK3β pathway in β-glucan–induced trained immunity.

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miR–9-5p induction is dependent on the Dectin-1/Akt/mTOR/GSK3β pathway i...
(A and B) Heatmap shows downregulated (red) and upregulated (green) miRNA from: PBMCs of healthy donors (A) and murine PBMCs (B) trained with β-glucan. The scale bar at the top ranges from red to green (low to high expression). RNA-seq was performed once in triplicate (n = 3). (C) miR–9-5p levels were determined using qPCR in β-glucan–trained monocytes at the indicated times (n = 3 independent experiments). (D) Dectin-1 (20 μg/mL) blocking impaired miR–9-5p expression in β-glucan–trained monocytes (n = 3 independent experiments). (E) miR–9-5p expression in β-glucan–trained monocytes in the presence of DMSO (control), rapamycin (100 nM), wortmanin (30 mM), MK2206 (10 μm), or ascorbate (50 μM) (n = 3 independent experiments). (F) Working model illustrating that the increased miR–9-5p induction occurs in a Dectin-1/Akt/mTOR/GSK3β–dependent manner. Human PBMCs from 5 donors; mouse blood mononuclear cells from 10 WT mice. Data represent means ± SEM. **P < 0.01, ***P < 0.001 by 1-way ANOVA/Dunnett’s multiple comparisons test (C, D, and E).