Department Pathology, Microbiology and Immunology, Vanderbilt University, Medical Center North, Nashville, TN, United States.
Department of Medicine, Vanderbilt University Medical Center, Medical Center North, Nashville, TN, United States.
Front Immunol. 2019 Nov 27;10:2740. doi: 10.3389/fimmu.2019.02740. eCollection 2019.
Women have increased prevalence of Th17-mediated autoimmune diseases, including lupus and multiple sclerosis, and severe asthma. While estradiol and progesterone increased IL-17A production in Th17 cells by inhibiting miRNA expression and increasing IL-23 receptor (IL-23R) expression, it remained unclear how estrogen signaling through the canonical nuclear receptors, estrogen receptor α (ERα) and/or ERβ, regulated this pathway. We hypothesized that estrogen signaling through ERα increased IL-23R expression and IL-17A production from Th17 cells. To test this hypothesis, naïve T cells from WT female, WT male, and female mice were differentiated into Th17 cells. IL-17A production and IL-23R expression were significantly increased in Th17 cells from WT female mice compared to Th17 cells from WT male mice. Deletion of ERα (), but not ERβ (), significantly decreased IL-17A production and IL-23R expression in Th17 cells by limiting IL-23R expression in a dependent manner. ERα deficiency also decreased Th17 cell proliferation as well as decreased T cell metabolism as measured by ATP-linked oxygen consumption rate and proton leakage. Further, we found that expression, a protein involved in mitochondrial respiration through assembly of cytochrome c oxidase in the electron transport chain, was increased in Th17 cells from WT female mice compared to Th17 cells from WT male and female mice. Inhibition of Cox20 decreased IL-17 production in Th17 cells from WT female mice. Combined these studies showed that ERα signaling increased IL-17A production in Th17 cells by upregulating IL-23R expression and promoting mitochondrial respiration and proliferation.
女性患有 Th17 介导的自身免疫性疾病（包括狼疮和多发性硬化症以及严重哮喘）的患病率增加。虽然雌二醇和孕酮通过抑制 microRNA 表达和增加 IL-23 受体（IL-23R）表达来增加 Th17 细胞中的 IL-17A 产生，但雌激素如何通过经典核受体（雌激素受体α（ERα）和/或 ERβ）信号传导来调节该途径仍不清楚。我们假设雌激素通过 ERα 信号传导增加 Th17 细胞中的 IL-23R 表达和 IL-17A 产生。为了验证这一假设，从 WT 雌性、WT 雄性和 ERα 缺失（）雌性小鼠的幼稚 T 细胞分化为 Th17 细胞。与 WT 雄性小鼠的 Th17 细胞相比，WT 雌性小鼠的 Th17 细胞中 IL-17A 产生和 IL-23R 表达显著增加。IL-23R 表达的依赖方式限制了 ERα 的缺失（），但不是 ERβ 的缺失（），显着降低了 Th17 细胞中的 IL-17A 产生和 IL-23R 表达。ERα 缺乏还降低了 Th17 细胞的增殖以及 T 细胞代谢，如通过与 ATP 相关的耗氧量和质子漏来测量的。此外，我们发现与电子传递链中线粒体呼吸有关的细胞色素 c 氧化酶组装的蛋白 Cox20 在 WT 雌性小鼠的 Th17 细胞中的表达高于 WT 雄性和 ERα 缺失（）雌性小鼠的 Th17 细胞。抑制 Cox20 减少了 WT 雌性小鼠 Th17 细胞中 IL-17 的产生。综合这些研究表明，ERα 信号通过上调 IL-23R 表达以及促进线粒体呼吸和增殖来增加 Th17 细胞中 IL-17A 的产生。
