Mir-9-5p Regulates Immunometabolic And Epigenetic Pathways In Beta-Glucan-Trained Immunity Via Idh3 Alpha

Trained immunity, induced by beta-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 3 alpha (IDH3 alpha) axis in trained immunity. We found that beta-glucan-trained miR-9-5p(-/-) monocytes showed decreased IL-1 beta, IL-6, and TNF-alpha 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 IDH3 alpha and reduced alpha-ketoglutarate (alpha-KG) levels to stabilize HIF-1 alpha, which promoted glycolysis. Accumulating succinate and fumarate via miR-9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. beta-Glucan-trained monocytes exhibited low IDH3 alpha levels, and IDH3 alpha overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3 alpha 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 IDH3 alpha act as critical metabolic and epigenetic switches in trained immunity.