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

miR-342，一种新的糖皮质激素反应性 miRNA，是 Foxp3 调节 T 细胞功能所必需的

• 批准号: 10671943
• 负责人: Booki Min
• 金额: $ 20万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-18 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10671943
• 关键词: 3' Untranslated Regions; Affect; Animal Model; Area; Autoimmunity; Binding; Biogenesis; Cell Lineage; Cell physiology; Chronic; Cytoplasm; Defect; Dexamethasone; Disease; Ensure; Experimental Autoimmune Encephalomyelitis; FOXP3 gene; Gene Expression; Generations; Genes; Glucocorticoids; Homeostasis; Human; Human Genome; Hypersensitivity; Immune; Immunity; Immunosuppression; Inflammation; Inflammatory; Inflammatory Response; Lead; Mediating; Metabolic; MicroRNAs; Modeling; Molecular; Mus; Nucleotides; Patients; Play; Predisposition; Proteins; Refractory; Regulation; Regulatory T-Lymphocyte; Reporting; Resistance; Ribonuclease III; Role; Serum; Steroid Resistance; Steroids; Testing; Therapeutic Effect; Untranslated RNA; allergic airway inflammation; attenuation; autoimmune inflammation; exosome; experimental study; immune activation; mortality; mouse model; novel; novel therapeutic intervention; overexpression; programs; response; therapy development

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.

摘要 Foxp 3+调节性T细胞（Treg）是免疫和耐受的中心调节因子。Treg生成缺陷 和/或功能导致小鼠和人类的致命性全身性自身免疫炎症，需要严格的 调节Treg稳态。因此，能够调节Treg功能的决定因子是免疫调节的主题。 至关重要。其中一个因素是微小RNA，一种已知调节基因表达的小的非编码RNA分子。 表情有大量证据表明，miRNA在Treg的生成和功能中发挥关键作用。 然而，我们对Treg衍生的miRNA调节Treg功能的机制的理解， 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 自身免疫和过敏。尽管用途广泛，但免疫抑制剂使用的精确免疫抑制机制 糖皮质激素在很大程度上仍然是难以捉摸的。我们最近报道，TdR在糖皮质激素治疗中是不可或缺的- 诱导治疗慢性炎症。从机制上讲，我们发现一种新型的miR-342是由 TcG中的糖皮质激素刺激以及miR-342靶向代谢调节因子Rictor以控制Treg代谢 编程.从初步研究中我们还发现，miR-342在膀胱癌中高表达， 通过地塞米松（Dex）刺激进一步增强。有趣的是，miR-342在Tumor中的表达似乎 对Treg抑制功能至关重要。此外，在Dex后的血清中也检测到miR-342 治疗令我们惊讶的是，在类固醇敏感的人中检测到了右旋糖酐诱导的血清miR-342，而在类固醇敏感的人中没有检测到。 抵抗性炎症基于这些令人信服的证据，我们提出了一个假设，即miR-342是一种 糖皮质激素诱导的miRNA在TCRs中起调节作用，TCRs控制炎症的能力。两 提出了具体目标。首先，我们将确定miR-342在Treg功能中的作用。两个新生成的 将使用其中Tclase缺乏或过表达miR-342的动物模型。第二，我们将研究 Treg衍生的miR-342在类固醇抵抗中的作用确定糖皮质激素诱导的 miR-342调节Treg功能将为开发适用于管理严重 炎症性疾病，包括类固醇抵抗。