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.

Loss of the transcriptional repressor Rev-erbα upregulates metabolism and proliferation in cultured mouse embryonic fibroblasts

“…Glycolysis stress tests were performed as an indicator of glycolytic levels as described previously 67 . MEF cells were seeded and incubated overnight as described for mitochondrial stress tests.…”

“…MEF cells were seeded and incubated overnight as described for mitochondrial stress tests. Proton efflux rate response following injections of the electron transport chain inhibitors rotenone/antimycin A and the glucose analog 2-DG was measured to determine basal and compensatory glycolysis as described previously 67 . Data were analyzed using the Seahorse Glycolytic Rate assay report generator, and basal glycolysis was calculated based on the differences in PER after 2-DG injection.…”

“…Nucleoside incorporation assays were performed as an index of proliferation as described previously 67 . Cells were seeded 24 h prior to assay start time.…”

“…Reagents from Abcam (catalog # ab65349) were used according to manufacturer protocols as described previously 67 . Three million WT and Rev-erbα KO cells were utilized for each biological measurement.…”

Fighting the SARS-CoV-2 pandemic requires a global approach to understanding the heterogeneity of vaccine responses

“…Studies have been performed to identify pre-vaccination signatures that predict vaccine efficacy and outcome [69][70][71][72] . Other studies have linked microbiota, metabolism, epigenetics and trained immunity shedding insight into the links of these critical pathways [73][74][75][76] . Thus, an individual's unique environmental and microbial exposure will define the nature of their future innate immune responses, including to vaccination, and potentially impact the efficacy of the generated immune responses.…”