Dehydroepiandrosterone (DHEA) is the most abundant circulating steroid hormone in humans, produced by the adrenals, the gonads and the brain. DHEA was previously shown to bind to the nerve growth factor receptor, tropomyosin-related kinase A (TrkA), and to thereby exert neuroprotective effects. Here we show that DHEA reduces microglia-mediated inflammation in an acute lipopolysaccharide-induced neuro-inflammation model in mice and in cultured microglia in vitro. DHEA regulates microglial inflammatory responses through phosphorylation of TrkA and subsequent activation of a pathway involving Akt1/Akt2 and cAMP response element-binding protein. The latter induces the expression of the histone 3 lysine 27 (H3K27) demethylase Jumonji d3 (Jmjd3), which thereby controls the expression of inflammation-related genes and microglial polarization. Together, our data indicate that DHEA-activated TrkA signaling is a potent regulator of microglia-mediated inflammation in a Jmjd3-dependent manner, thereby providing the platform for potential future therapeutic interventions in neuro-inflammatory pathologies.

中文翻译：

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DHEA通过激活TrkA-Akt1 / 2-CREB-Jmjd3途径抑制急性小胶质细胞介导的炎症。

脱氢表雄酮（DHEA）是人类中最丰富的循环类固醇激素，由肾上腺，性腺和大脑产生。DHEA先前已证明与神经生长因子受体，原肌球蛋白相关的激酶A（TrkA）结合，从而发挥神经保护作用。在这里，我们显示DHEA在小鼠和体外培养的小胶质细胞中，在急性脂多糖诱导的神经炎症模型中减少了小胶质细胞介导的炎症。DHEA通过TrkA的磷酸化和随后激活涉及Akt1 / Akt2和cAMP反应元件结合蛋白的途径来调节小胶质细胞炎症反应。后者诱导组蛋白3赖氨酸27（H3K27）脱甲基酶Jumonji d3（Jmjd3）的表达，从而控制炎症相关基因和小胶质细胞极化的表达。一起，