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

基本信息

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
项目类别：
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&apos 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

Anti-Inflammatory Agents Anti-inflammatory Antigens Bacteria Binding Biological Cells Chronic Colitis Communication Complementary Medicine Complex Crohn&apos 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

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项目摘要

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（由适用提供）：该提案的总体目标是定义可食用的植物外泌体非编码小RNA（NC-SRNA）在使用葡萄糖硫酸钠（DSS）诱导的结肠炎和其他三种其他肠炎性相关的小鼠模型中使用葡萄糖硫酸钠（DSS）预防肠道注射的作用。尽管支持大多数可食用植物作为饮食的一部分的有益效果的证据，但具有特定植物补充剂是有益的证据是有争议的，而且基本机制尚不清楚。面临的挑战是要隔离和表征特定自然产品中包含的基本功能单元的生物学活性，以确定它是否以及如何以有益的方式使用其对宿主的细胞和分子影响。我们最近发表的数据（1-5）表明，包括葡萄柚和姜在内的许多可食用植物中存在的外泌体样纳米颗粒（ELN）具有抗炎特性。饲喂葡萄柚ELN（FELNS）的小鼠受到DSS诱导的小鼠结肠炎的保护。肠道巨噬细胞对FELN进行抑制，抑制了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，FELNS具有高水平的特异性NC-SRNA，这些NC-SRNA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失活有关。与Naringin复合的特定FELN NC-SRNA与MiR155结合，随后防止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，生姜ELN NC-SRNA促进了在稳态和炎症条件下在层次巨噬细胞中促进IL-10的产生。因此，我们假设携带NC-SRNA生物活性复合物的植物ELS被肠道巨噬细胞所吸收，然后与炎症性microRNA结合，从而抑制慢性炎症细胞因子的诱导，从而防止慢性肠道炎症。我们的假设将在体外和体内进行测试，以确定：（1）FELN是否被肠道巨噬细胞占据，导致通过NC-SRNA-155介导的抗炎作用诱导耐受性树突状细胞（DCS），因为DC自DC通过DC通过肠道免疫耐受性和脑托管而与无肠道造成肠道造成的抗脑膜化至关重要。（2）调节抗炎NC-SRNA-155中分选巨噬细胞外泌体的因素；（3）诱导巨噬细胞中表达的抗炎IL-10所必需的姜汁NC-SRNA（S）。靶向肠道炎性细胞的ELNS复合物的证明将是了解植物王国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。生成的数据应为患者选择不同类型的植物中的特定植物的特定ELN提供基础。