miR-342, a novel glucocorticoid-responsive miRNA necessary for Foxp3+ regulatory T cell function

摘要 Foxp3调节性T细胞(Treg)是免疫和耐受的中枢调节细胞。Treg生成中的缺陷 和/或功能导致小鼠和人类的致命性全身性自身免疫性炎症，需要严格的 调节Treg动态平衡。因此，确定能够调节Treg功能的因素是一个主题 非常重要。其中一个因素是microRNA，这是一种已知的调节基因的非编码小RNA分子 表情。有大量证据表明miRNAs在Treg的产生和功能中起着关键作用。 然而，我们对Treg衍生的miRNA调节Treg功能的机制的理解是 相对有限。糖皮质激素是许多炎症性疾病的一线治疗选择，包括 自身免疫力和过敏症。尽管被广泛使用，但由 糖皮质激素在很大程度上仍然难以捉摸。我们最近报道，在糖皮质激素治疗过程中，Tregs是必不可少的- 慢性炎症的诱导治疗。从机理上讲，我们发现一种新的miR-342是由 糖皮质激素对Treg的刺激以及miR-342靶向代谢调节剂Rictor来控制Treg代谢 编程。从初步的研究中我们还发现miR-342在Tregs中高表达，并且它 地塞米松(Dex)刺激进一步增强。有趣的是，miR-342在Treg中的表达似乎 对Treg抑制功能至关重要。此外，在地塞米松后的血清中也检测到miR-342 治疗。令我们惊讶的是，地塞米松诱导的血清miR-342在类固醇敏感的患者中被检测到，但在类固醇敏感的患者中没有检测到。 抗炎。基于令人信服的证据，我们提出了miR-342是一种 糖皮质激素诱导的Treg中的miRNA在Treg控制炎症的能力中发挥调节作用。二 提出了具体的目标。首先，我们将确定miR-342在Treg功能中的作用。两个新产生的 Tregs缺乏或过度表达miR-342的动物模型将被使用。第二，我们将研究 Treg来源的miR-342对类固醇耐药。糖皮质激素诱导机制的研究进展 MIR-342调节Treg功能将为开发适用于治疗重症的药物打开新的机会 炎症状况，包括类固醇抵抗。

Abstract Foxp3+ regulatory T cells (Treg) are the central regulators of immunity and tolerance. Defects in Treg generation and/or functions lead to lethal systemic autoimmune inflammation in both mice and human, demanding a tight regulation of Treg homeostasis. Determining factors capable of modulating Treg function is thus a subject of utmost importance. Among the factors is microRNA, a small non-coding RNA molecule known to regulate gene expression. There is plethora of evidence that miRNAs play a critical role in Treg generation and functions. However, our understanding the mechanisms by which Treg-derived miRNA modulates Treg functions is relatively limited. Glucocorticoids are the frontline treatment option for many inflammatory diseases, including autoimmunity and allergy. Despite the broad use, the precise immune suppressive mechanisms used by glucocorticoids remain largely elusive. We recently reported that Tregs are indispensable during glucocorticoid- induced treatment of chronic inflammation. Mechanistically, we uncovered that a novel miR-342 is induced by glucocorticoid stimulation in Tregs and that miR-342 targets metabolic regulator, Rictor, to control Treg metabolic programming. From the preliminary studies we also found that miR-342 is highly expressed in Tregs and that it is further enhanced by dexamethasone (Dex) stimulation. Interestingly, miR-342 expression in Tregs appears to be critical for Treg suppressive function. Moreover, miR-342 was also detected in the serum following Dex treatment. To our surprise, Dex-induced serum miR-342 was detected in steroid-sensitive but not in steroid- resistant inflammation. Based on the compelling evidence, we propose the hypothesis that miR-342 is a glucocorticoid-induced miRNA in Tregs that plays a regulatory role in Tregs’ ability to control inflammation. Two specific aims are proposed. First, we will determine the role of miR-342 in Treg functions. Two newly generated animal models in which Tregs lack or overexpress miR-342 will be used. Second, we will examine the role of Treg-derived miR-342 in steroid resistance. Identification of the mechanisms by which glucocorticoid-induced miR-342 regulates Treg functions will open novel opportunities to develop therapies applicable to manage severe inflammatory conditions including steroid resistance.