miR-9-5p regulates immunometabolic and epigenetic pathways in β-glucan-trained immunity via IDH3α.
miR-9-5p regulates immunometabolic and epigenetic pathways in β-glucan-trained immunity via IDH3α.
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miR-9- 5 p通过IDH 3 α调节β-葡聚糖训练的免疫中的免疫代谢和表观遗传途径。
DOI：
10.1172/jci.insight.144260
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发表时间：
2021-05-10
期刊：
影响因子：
8
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Su H;Liang Z;Weng S;Sun C;Huang J;Zhang T;Wang X;Wu S;Zhang Z;Zhang Y;Gong Q;Xu Y
单核细胞中β-葡聚糖诱导的训练免疫通过激活代谢途径介导，导致细胞功能程序的表观遗传重新布线;然而，这些变化背后的分子机制仍不清楚。在这里，我们报告了在训练免疫中由miR-9- 5 p-isocitrate dehydrogenase 3α（IDH 3 α）轴介导的关键免疫代谢和表观遗传途径。我们发现β-葡聚糖训练的miR-9- 5 p-/-单核细胞在LPS刺激后显示IL-1β、IL-6和TNF-α的产生减少。训练的miR-9- 5 p-/-小鼠在体内再激发时产生降低水平的促炎细胞因子，并且对白色念珠菌感染的保护更差。miR-9- 5 p靶向IDH 3 α并降低α-酮戊二酸（α-KG）水平以稳定HIF-1α，从而促进糖酵解。通过miR-9- 5 p作用积累琥珀酸和富马酸整合免疫代谢回路，通过抑制KDM 5脱甲基酶诱导组蛋白修饰。β-葡聚糖训练的单核细胞表现出较低的IDH 3 α水平，IDH 3 α过表达阻断了单核细胞对训练免疫的诱导。来自常染色体隐性视网膜色素变性患者的IDH 3 α变体单核细胞在免疫代谢和表观遗传水平上显示出训练的免疫表型。这些发现表明，miR-9- 5 p和IDH 3 α在训练免疫中充当关键的代谢和表观遗传开关。
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.