Dataset Information

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.

SUBMITTER: Su H

PROVIDER: S-EPMC8262351 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Su Haibo H Liang Zhongping Z Weng ShuFeng S Sun Chaonan C Huang Jiaxin J Zhang TianRan T Wang Xialian X Wu Shanshan S Zhang Zhi Z Zhang Yiqi Y Gong Qing Q Xu Ying Y

JCI insight 20210510 9

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 st ...[more]

PMID: 33986196

Similar Datasets

Project description:Background: Innate immune memory, also termed "trained immunity", is thought to protect against experimental models of infection, including sepsis. Trained immunity via reprogramming monocytes/macrophages has been reported to result in enhanced inflammatory status and antimicrobial activity against infection in sepsis. However, a safe and efficient way to induce trained immunity remains unclear. Methods: β-glucan is a prototypical agonist for inducing trained immunity. Ferumoxytol, superparamagnetic iron oxide (SPIO) with low cytotoxicity, has been approved by FDA for clinical use. We synthesized novel nanoparticles BSNPs by coupling β-glucan with SPIO. BSNPs were further conjugated with fluorescein for quantitative analysis and trace detection of β-glucan on BSNPs. Inflammatory cytokine levels were measured by ELISA and qRT-PCR, and the phagocytosis of macrophages was detected by flow cytometry and confocal microscopy. The therapeutic effect of BSNPs was evaluated on the well-established sepsis mouse model induced by both clinical Escherichia coli (E. coli) and cecal ligation and puncture (CLP). Results: BSNPs were synthesized successfully with a 3:20 mass ratio of β-glucan and SPIO on BSNPs, which were mainly internalized by macrophages and accumulated in the lungs and livers of mice. BSNPs effectively reprogrammed macrophages to enhance the production of trained immunity markers and phagocytosis toward bacteria. BSNP-induced trained immunity protected mice against sepsis caused by E. coli and CLP and also against secondary infection. We found that BSNP treatment elevated Akt, S6, and 4EBP phosphorylation, while mTOR inhibitors decreased the trained immunity markers and phagocytosis enhanced by BSNPs. Furthermore, the PCR Array analysis revealed Igf1, Sesn1, Vegfa, and Rps6ka5 as possible key regulators of mTOR signaling during trained immunity. BSNP-induced trained immunity mainly regulated cellular signal transduction, protein modification, and cell cycle by modulating ATP binding and the kinase activity. Our results indicated that BSNPs induced trained immunity in an mTOR-dependent manner. Conclusion: Our data highlight that the trained immunity of macrophages is an effective strategy against sepsis and suggest that BSNPs are a powerful tool for inducing trained immunity to prevent and treat sepsis and secondary infections.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets