fumarates and Candidiasis

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.

Topics: Animals; beta-Glucans; Candida albicans; Candidiasis; Epigenesis, Genetic; Fumarates; Glycolysis; Hypoxia-Inducible Factor 1, alpha Subunit; Immunity, Innate; Immunologic Memory; Interleukin-1beta; Interleukin-6; Isocitrate Dehydrogenase; Ketoglutaric Acids; Lipopolysaccharides; Metabolic Networks and Pathways; Mice; Mice, Knockout; MicroRNAs; Monocytes; Retinitis Pigmentosa; Succinic Acid; Tumor Necrosis Factor-alpha

An examination was made on the effect of fumaric acid on an experimental systemic candidiasis. Male ICR mice were innoculated into the tail veins with 10(6) yeast cells of Candida albicans and treated with daily intraperitoneal injections of fumaric acid at the dose of 40 mg/kg/d. The results indicated that the administration of fumaric acid was effective in prolonging the survival of animals after the fungal challenge and prevented one-fifth of the treated animals from dying of candidiasis.

Topics: Animals; Antifungal Agents; Candidiasis; Fumarates; Male; Mice; Mice, Inbred ICR