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 5

miR–9-5p regulates the molecular, metabolic, and epigenetic hallmarks of trained immunity.

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miR–9-5p regulates the molecular, metabolic, and epigenetic hallmarks of...
(A–D) Accumulation of citrate, malate, and oxoglutarate (A); glutamate (B); total content of α-KG, succinate, and fumarate (C); and the ratio of α-KG to succinate and fumarate (D) were determined using the cell lysates on day 6 in β-glucan versus nontrained monocytes from WT or miR–9-5p–/– mice (n = 3 independent experiments). (E) Enzymes involved in glutamate conversion into α-KG were screened using qPCR (n = 5 independent experiments). (F) ODD luciferase activity was measured in β-glucan–trained versus nontrained monocytes from WT or miR–9-5p–/– mice (n = 5 independent experiments). (G) ODD luciferase activity was measured in monocytes treated with 100 μM α-KG, 100 μM fumarate, or mixtures of α-KG (100 μM) with 100 μM fumarate under training condition; the values were normalized to control (n = 5 independent experiments). (H) The hydroxylation level of HIF-1α was detected in β-glucan–trained monocytes from WT or miR–9-5p–/– mice, using an antibody against hydroxylated HIF-1α at proline 564 (n = 3 independent experiments). (I and J) PHD1, but not PHD2, regulates HIF-1α stability (n = 3 independent experiments). (K) KDM5 activity was determined in β-glucan–trained monocytes from WT or miR–9-5p–/– mice (n = 6 independent experiments). (L) H3K4me3 level was determined at the promoter sites of HK2, GLUT1, TNFA, and IL6 (n = 3 independent experiments). In A–G, K, and L, data represent means ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 by 1-way ANOVA/Tukey’s multiple comparisons test (A–F, K, and L); ***P < 0.001 by 2-tailed Student’s t test (G). Unprocessed original scans of blots are shown in Supplemental Figure 11.