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.
View: Text | PDF | Corrigendum
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

×

Figure 6

miR–9-5p regulates the expression of IDH3α.

Options: View larger image (or click on image) Download as PowerPoint
miR–9-5p regulates the expression of IDH3α. (A) Activity of IDH, SDH, FH...
(A) Activity of IDH, SDH, FH, and OGDH in β-glucan–trained monocytes from WT or miR–9-5p–/– mice (n = 3 independent experiments). (B) miR–9-5p regulates IDH3α expression. Left: luciferase activity of IDH3α 3′UTR. Right: luciferase activity in WT or mutant IDH3α 3′UTR groups. The nucleotides indicated in red for the IDH3α seed sequence were mutated to complementary nucleotides (n = 3 independent experiments). (C) qPCR analysis of IDH3α, IDH2, SDHB, and FH1 in β-glucan–trained monocytes from WT or miR–9-5p–/– mice (n = 3 independent experiments). (D) Western blot analysis of IDH3α, FH, SDHB, and IDH2 expression in β-glucan–trained monocytes from WT or miR–9-5p–/– mice (n = 3 independent experiments). (E) Western blot analysis of IDH3α expression in β-glucan–trained monocytes from WT or miR–9-5p–/– mice in the presence of 10 μM MG132 (proteasome inhibitor) or 50 μM chloroquine (lysosome inhibitor) (n = 3 independent experiments). (F) IDH3α expression in monocytes from WT or miR–9-5p–/– mice transfected with miR–9-5p overexpression or a control under β-glucan training (n = 3 independent experiments). (G) IDH3α expression determined by Western blot in monocytes from trained radiation chimeras and WT and miR–9-5p–/– mice, according to Figure 3E (n = 3 independent experiments). Data represent means ± SEM. **P < 0.01, ***P < 0.001 by 2-tailed Student’s t test (A, C, and F); **P < 0.01 by 1-way ANOVA/Tukey’s multiple comparisons test (B). Unprocessed original scans of blots are shown in Supplemental Figure 11.