miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α
Haibo Su, Zhongping Liang, ShuFeng Weng, Chaonan Sun, Jiaxin Huang, TianRan Zhang, Xialian Wang, Shanshan Wu, Zhi Zhang, Yiqi Zhang, Qing Gong, Ying Xu
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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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 3

miR–9-5p deletion impairs trained immunity in vivo.

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miR–9-5p deletion impairs trained immunity in vivo. (A) In vivo training...
(A) In vivo training mouse model via 2 i.p. and secondary i.p. β-glucan injections. (B) LPS challenge for measuring serum cytokines (n = 3 pooled experiments). (C) In vivo training mouse model similar to A but with secondary C. albicans lethal infection. (D) Survival curve, according to C. (E) List of radiation chimeras used in this study and experimental design. (F) Survival curves of radiation chimeras, WT, and miR–9-5p–/– mice trained with β-glucan, followed with a lethal C. albican infection, according to E. (G) The production of TNF-α was determined in lethally infected monocytes from trained radiation chimeras and WT and miR–9-5p–/– mice, according to E. (H) Kidney fungal burden was determined in lethally infected monocytes from trained radiation chimeras and WT and miR–9-5p–/– mice, according to E. In B, G, and H, single dots correspond to individual mice; means ± SEM of 2 or 3 pooled experiments are shown, including 5–6 mice per condition. **P < 0.01 by 2-tailed Student’s t test comparing WT and miR–9-5p–/– (B); *P < 0.05, **P < 0.01, ***P < 0.001 by 1-way ANOVA/Tukey’s multiple comparisons test (bottom) (G and H). A pool of 2 experiments is shown, including 6–13 mice per group as indicated. **P < 0.01, ***P < 0.001 by log-rank test (D and F).