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 8

Monocytes with an IDH3α mutation (p.Ala-175-Val) from patients with autosomal recessive retinitis pigmentosa (ArRP) show a trained immunity phenotype.

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Monocytes with an IDH3α mutation (p.Ala-175-Val) from patients with auto...
(A) Monocytes from patients with autosomal recessive retinitis pigmentosa (ArRP), who had the IDH3α (p.Ala-175-Val) mutation, and matching healthy volunteers were exposed ex vivo to several ligands for 24 hours. Cytokine expression levels were measured in the supernatants (n = 5 independent experiments). (B) Heatmap of individual donors for genes that show LPS responses in controls and patients with ArRP who had IDH3α (p.Ala-175-Val) mutation. Monocytes were either untreated or stimulated for 24 hours with media or LPS. RNA-seq was performed once in triplicate (n = 3 versus 3). (C) Pathway associated with genes that show higher expression in ArRP patients monocytes exposed to 24-hour RPMI compared with controls (n = 3 versus 3). (D) H3K4me3 levels were determined at the promoter sites of TNFA, IL-6, HK2, and GLUT1 in ArRP patient monocytes exposed to 24-hour RPMI compared with controls (n = 4 independent experiments). Data are shown as means ± SEM, *P < 0.05, **P < 0.01, or ***P < 0.001 by 2-tailed Student’s t test (A and D).