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miR–9-5p regulates immunometabolic and epigenetic pathways in β-glucan–trained immunity via IDH3α
- Source :
- JCI Insight, JCI Insight, Vol 6, Iss 9 (2021)
- Publication Year :
- 2021
- Publisher :
- American Society for Clinical Investigation, 2021.
-
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.
- Subjects :
- Lipopolysaccharides
0301 basic medicine
Epigenomics
beta-Glucans
Interleukin-1beta
Immunology
Succinic Acid
Inflammation
Stimulation
Biology
Monocytes
Proinflammatory cytokine
Epigenesis, Genetic
Mice
03 medical and health sciences
0302 clinical medicine
Fumarates
Immunity
Candida albicans
medicine
Animals
Glycolysis
Epigenetics
Mice, Knockout
Innate immunity
Innate immune system
Interleukin-6
Tumor Necrosis Factor-alpha
Candidiasis
General Medicine
Hypoxia-Inducible Factor 1, alpha Subunit
Immunity, Innate
Isocitrate Dehydrogenase
Cell biology
MicroRNAs
030104 developmental biology
Histone
030220 oncology & carcinogenesis
biology.protein
Medicine
Ketoglutaric Acids
medicine.symptom
Immunologic Memory
Metabolic Networks and Pathways
Retinitis Pigmentosa
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 6
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....42aff7076cfee891f7e871e85d1806e1