Plant exosomes non-coding RNA-mediated anti-inflammatory mechanisms

植物外泌体非编码RNA介导的抗炎机制

• 批准号: 9036506
• 负责人: HUANG-GE ZHANG
• 金额: $ 47.3万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036506
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Bacteria; Binding; Biological; Cells; Chronic; Colitis; Communication; Complementary Medicine; Complex; Crohn' s disease; Data; Dendritic Cells; Diet; Disease; Edible Plants; Encapsulated; Escherichia; Escherichia coli; Exposure to; Food; Foundations; Genes; Ginger; Goals; Grapefruit; Health; Heating; Homeostasis; Immune; Immune Tolerance; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Inflammatory disease of the intestine; Interleukin-1; Interleukin-1 beta; Interleukin-10; Interleukin-6; Intestines; Investigation; Lamina Propria; Lipids; Literature; Macrophage Activation; Mediating; MicroRNAs; Modeling; Molecular; Mononuclear; Mucous Membrane; Mus; Myeloid Cell Activation; Natural Products; Oral Administration; Pathway interactions; Patients; Phagocytes; Plant Extracts; Plants; Play; Prevention; Production; Property; Proteins; Publishing; RNA Binding; Role; Sampling; Signal Transduction; Small RNA; Sodium Dextran Sulfate; Sorting - Cell Movement; TNF gene; Testing; Untranslated RNA; Untranslated Regions; base; bioactive natural products; cytokine; exosome; feeding; fruits and vegetables; in vitro testing; in vivo; killings; lymph nodes; macrophage; mouse model; nanoparticle; prevent; public health relevance; research study; transcription factor; uptake

 DESCRIPTION (provided by applicant): The overall goal of this proposal is to define the role of edible plant exosomal non-coding small RNA (nc-sRNA) in the prevention of gut inflammation using the dextran sulfate sodium (DSS) induced colitis and three other gut inflammatory related mouse models. Although evidence is supportive of the beneficial effects for most edible plants taken as part of the diet, the evidence that specific plant-based supplements are beneficial is controversial, and the underlying mechanisms are not clear. The challenge is to isolate and characterize the biological activities of the essential functional unit contained in specific naturl products to determine if and how it's cellular and molecular effects on the host can be used in a beneficial manner. Our recently published data (1-5) indicates that exosome-like nanoparticles (ELNs) present in a number of edible plants including grapefruit and ginger have anti-inflammatory properties. Mice fed grapefruit ELNs (FELNs) are protected against DSS induced mouse colitis. Up take of FELNs by intestinal macrophages inhibits the release of IL-1β and IL-6 and the induction of HO-1 and IL-10 expression. Our preliminary data further indicate that FELNs carry high levels of specific nc-sRNA that inhibit the induction of proinflammatory cytokines by targeting intestinal macrophages. The nc-sRNA is associated with inactivation of macrophage miR155. A specific FELN nc-sRNA complexed with naringin binds to miR155 and subsequently prevents miR155 binding to 3-UTRs of certain anti-inflammatory genes, thus inhibiting the induction of proinflammatory cytokines. We have also demonstrated that ginger ELN nc-sRNAs promotes the production of IL-10 in lamina propria macrophages under steady-state as well as inflammatory conditions. Therefore, we hypothesize that plant ELNs carrying the nc-sRNA bioactive complex are taken up by intestinal macrophages and subsequently bind to inflammatory microRNAs, resulting in inhibition of induction of chronic inflammation cytokines, thereby preventing chronic intestinal inflammation. Our hypothesis will be tested in vitro and in vivo to determine: (1) whether FELN taken up by intestinal macrophages leads to induction of tolerant dendritic cells (DCs) through nc-sRNA-155 mediated anti-inflammatory effects since DCs are critical for gut immune tolerance and homeostasis through cross-talk with intestinal macrophages; (2) the factors that regulate sorting of anti-inflammatory nc-sRNA-155 into macrophage exosomes; and (3) which ginger ELNs nc-sRNA(s) are required for induction of anti- inflammatory IL-10 expressed in macrophages. Demonstration of the ELNs complex targeting to gut inflammatory cells would be a significant step forward in the understanding of how the plant kingdom interacts with the mammalian species to regulate anti-inflammatory responses through ELNs. The data generated should provide a foundation for selecting specific ELNs from different types of plants for personalized complementary medicine for patients and determine whether oral administration of a customized exosome isolated from different plants will have a synergistic/additive effect on prevention or treatment of disease.

 描述（由申请人提供）：该提案的总体目标是利用葡聚糖硫酸钠（DSS）诱导的结肠炎和其他三种肠道炎症相关小鼠模型，确定可食用植物外泌体非编码小RNA（nc-sRNA）在预防肠道炎症中的作用。尽管有证据支持大多数食用植物作为饮食的一部分具有有益作用，但特定植物性补充剂有益的证据存在争议，而且其潜在机制尚不清楚。面临的挑战是分离和表征特定天然产品中所含基本功能单元的生物活性，以确定是否以及如何以有益的方式利用其对宿主的细胞和分子影响。我们最近发布的数据 (1-5) 表明，葡萄柚和生姜等多种食用植物中存在的外泌体样纳米颗粒 (ELN) 具有抗炎特性。喂食葡萄柚 ELN (FELN) 的小鼠可以免受 DSS 诱导的小鼠结肠炎的影响。肠道巨噬细胞摄取 FELN 会抑制 IL-1β 和 IL-6 的释放以及 HO-1 和 IL-10 表达的诱导。我们的初步数据进一步表明，FELN 携带高水平的特异性 nc-sRNA，可通过靶向肠道巨噬细胞来抑制促炎细胞因子的诱导。 nc-sRNA 与巨噬细胞 miR155 失活相关。与柚皮苷复合的特定 FELN nc-sRNA 与 miR155 结合，随后阻止 miR155 与某些抗炎基因的 3-UTR 结合，从而抑制促炎细胞因子的诱导。我们还证明，姜 ELN nc-sRNA 在稳态和炎症条件下可促进固有层巨噬细胞产生 IL-10。因此，我们假设携带nc-sRNA生物活性复合物的植物ELN被肠道巨噬细胞摄取，随后与炎症性microRNA结合，从而抑制慢性炎症细胞因子的诱导，从而预防慢性肠道炎症。我们的假设将在体外和体内进行测试，以确定：（1）肠道巨噬细胞摄取的 FELN 是否会通过 nc-sRNA-155 介导的抗炎作用诱导耐受树突状细胞（DC），因为 DC 通过与肠道巨噬细胞的串扰对肠道免疫耐受和稳态至关重要； (2)调节抗炎性nc-sRNA-155分选至巨噬细胞外泌体的因素； (3)哪些生姜ELN nc-sRNA是诱导巨噬细胞中表达的抗炎IL-10所必需的。证明针对肠道炎症细胞的 ELN 复合物将是理解植物界如何与哺乳动物物种相互作用以通过 ELN 调节抗炎反应的重要一步。生成的数据将为从不同类型的植物中选择特定的 ELN 为患者提供个性化补充医学奠定基础，并确定口服从不同植物中分离的定制外泌体是否会对疾病的预防或治疗产生协同/累加效应。