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.
Highlights
Trained immunity, the nonspecific memory of the innate immune system, has been present by a wide variety of recent — and older — studies in plants, invertebrates, and mammals [1, 2]
We showed that miR–9-5p was abundantly expressed in β-glucan–trained monocytes via the Dectin-1/Akt/mTOR/GSK3β pathway and that it contributed to trained immunity via isocitrate dehydrogenase 3α (IDH3α)
To further investigate the signaling involved in induction of miR–9-5p, we trained monocytes with β-glucan in the presence of a selective mTOR inhibitor, Akt inhibitor, or HIF-1α inhibitor
Summary
The nonspecific memory of the innate immune system, has been present by a wide variety of recent — and older — studies in plants, invertebrates, and mammals [1, 2]. Trained monocytes have high glucose consumption, lactate production, and NAD+/NADH ratio, displaying a shift from oxidative phosphorylation to aerobic glycolysis (Warburg effect), depending on the activation of mTOR through the Dectin-1/Akt/HIF-1α pathway [6]. Causal to the enhanced inflammatory response in trained immunity is the increased deposition of histone marks that are positively correlated with transcription at the promoters of key immune genes. Accumulation of fumarate contributes to trained immunity phenotype by inhibiting KDM5 histone demethylases (responsible for H3K4me demethylation) and, influencing epigenetic reprogramming, whereas α-ketoglutarate (α-KG) counteracts this effect [7]. Molecular mechanisms underlying cellular metabolism reprogramming, with a shift from oxidative phosphorylation to aerobic glycolysis and the accumulation of metabolites from the TCA cycle, have not been fully deciphered, thereby impairing understanding of trained immunity
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