Suppressing inflammation and boosting humoral immunity with n-3 PUFAs

用 n-3 PUFA 抑制炎症并增强体液免疫

• 批准号: 9349651
• 负责人: SAAME R SHAIKH
• 金额: $ 16.12万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349651
• 关键词: Adipose tissue; Agreement; Anti-Inflammatory Agents; Anti-inflammatory; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocytes; Biological Assay; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Chronic; Clinic; Clinical; Complementary and alternative medicine; Data; Development; Diet; Disease; Docosahexaenoic Acids; Equilibrium; Esters; Fatty Acids; Fish Oils; Foundations; G-Protein-Coupled Receptors; General Population; Genetic; Goals; Health; Human; Humoral Immunities; Immune response; Immune system; Immunity; Immunosuppression; Individual; Inflammation; Inflammatory; Influenza; Interleukin-10; Knowledge; Mediating; Membrane; Mission; Modality; Modeling; Molecular; Mus; N-3 polyunsaturated fatty acid; Obese Mice; Obesity; Phenotype; Polyunsaturated Fatty Acids; Population; Proteins; Public Health; Recommendation; Regulatory T-Lymphocyte; Research; Signal Transduction; Testing; Th2 Cells; Translating; Translations; Triglycerides; United States National Institutes of Health; Viral Tumor Antigens; Virus Diseases; cell type; clinical application; cytokine; fatty acid supplementation; imaging modality; immunological synapse; in vivo; innovation; lipid mediator; mouse model; murine antibody; novel; programs; response; sensor; sound

 DESCRIPTION (provided by applicant): The n-3 polyunsaturated fatty acids (PUFA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid, are bioactive molecules with clinical applications for suppressing chronic inflammation. A major obstacle in the translation of n-3 PUFAs into the clinic is a limited understanding of the mechanisms by which n-3 PUFAs regulate inflammation and moreover, the consequences of n-3 PUFAs on other aspects of the immune system. We have discovered n-3 PUFAs boost murine immune responses from B cells, which we propose is a result of n-3 PUFAs exerting immunosuppressive effects on antigen presenting cells and CD4+ T cells. The data raise the exciting possibility that n-3 PUFAs can be used to simultaneously suppress cell-mediated inflammation and enhance humoral immunity in select diseases. The long-term goal of our research program is to establish the efficacy of n-3 PUFAs on immunity for the general public and for specific clinical populations. The current objectives are to determine the individual and combined efficacy of EPA and DHA in regulating inflammatory cytokines and humoral immunity in lean and obese mice. The rationale for focusing on obesity is that obese individuals display, in addition to chronic inflammation, poor humoral immunity. The central hypothesis is that n-3 PUFAs generate CD4+ Th2 cytokines that boost B cell activation and antibody production. We will also test the additional hypothesis that n-3 PUFAs enhance Th2 cytokines and B cell activity by targeting the G-protein coupled receptor (GPR) 120, an n-3 PUFA sensor. Aim 1 will establish n-3 PUFAs suppress Th1/Th17 cytokines and enhance Th2 cytokines and Tregs in lean mice. Aim 1 will then determine if n-3 PUFAs boost Th2 cytokines by targeting the immunological synapse and GPR120 of select cell types. Aim 2 will determine how n-3 PUFAs boost humoral immunity of lean mice. Aim 2 will first elucidate how elevated Th2 cytokines, in response to n-3 PUFAs, enhance B cell activity. Aim 2 will then dissect the contribution of additional mechanisms by which n-3 PUFAs could directly enhance B cell activity. These include n-3 PUFAs stimulating B cell GPR120 signaling and generating pro-resolving lipid mediators. Aim 3 will establish the efficacy of n-3 PUFAs in rescuing the decrement in antibody production of obese mice in response to several antigens including influenza. Aim 3 will also establish the efficacy of n-3 PUFAs on suppressing inflammation by enhancing select adipose specific B cells in a GPR120 dependent manner. The approach will rely on immunological assays, genetic mouse models, lipidomics, and biophysical imaging methods. The proposal is significant because it will define the efficacy of EPA+DHA (modeling over-the-counter and prescription supplements) and the individual activities of EPA and DHA on inflammation and humoral immunity in lean and obese mice. The research is innovative because it tests novel mechanisms using complementary approaches to challenge the general paradigm that n-3 PUFAs only have utility for suppressing or resolving inflammation. Completion of the project will provide a foundation for studies with select n-3 PUFAs on immunity in humans.

 描述（由申请人提供）：n-3 多不饱和脂肪酸（PUFA）、二十碳五烯酸（EPA）和二十二碳六烯酸（DHA）是生物活性分子，具有抑制慢性炎症的临床应用，是n-3 转化的主要障碍。 PUFA 进入临床后，人们对 n-3 PUFA 调节炎症的机制以及 n-3 PUFA 对炎症其他方面的影响了解有限。我们发现 n-3 PUFA 可以增强小鼠 B 细胞的免疫反应，我们认为这是 n-3 PUFA 对抗原呈递细胞和 CD4+ T 细胞发挥免疫抑制作用的结果。 -3 PUFA 可用于同时抑制细胞介导的炎症并增强特定疾病的体液免疫。我们研究计划的长期目标是确定 n-3 PUFA 对普通公众和免疫系统的功效。目前的目标是确定 EPA 和 DHA 在调节瘦小鼠和肥胖小鼠的炎症细胞因子和体液免疫方面的个体和联合功效。 ，体液免疫能力差。核心假设是 n-3 PUFA 产生 CD4+ Th2 细胞因子，促进 B 细胞活化和抗体产生。我们还将测试 n-3 PUFA 通过以下方式增强 Th2 细胞因子和 B 细胞活性的额外假设。以 G 蛋白偶联受体 (GPR) 120 为目标，n-3 PUFA 传感器 Aim 1 将建立 n-3 PUFA 抑制 Th1/Th17 细胞因子并增强瘦小鼠中的 Th2 细胞因子和 Tregs。 3 PUFA 通过靶向选定细胞类型的免疫突触和 GPR120 来增强 Th2 细胞因子 目标 2 将确定 n-3 PUFA 如何增强体液免疫。目标 2 将首先阐明 n-3 PUFA 升高的 Th2 细胞因子如何增强 B 细胞活性，然后剖析 n-3 PUFA 直接增强 B 细胞活性的其他机制。包括 n-3 PUFA 刺激 B 细胞 GPR120 信号传导并产生促解决脂质介质 目标 3 将确定 n-3 PUFA 在挽救减脂方面的功效。 Aim 3 还将通过以 GPR120 依赖性方式增强选定的脂肪特异性 B 细胞来确定 n-3 PUFA 抑制炎症的功效。该提案具有重要意义，因为它将定义 EPA+DHA（模拟非处方药和处方补充剂）的功效以及 EPA 和 DHA 的个体活性。 DHA 对瘦小鼠和肥胖小鼠的炎症和体液免疫的影响 该研究具有创新性，因为它使用补充方法测试了新机制，挑战了 n-3 PUFA 仅具有抑制或解决炎症作用的一般范式。为研究选定的 n-3 PUFA 对人类免疫力的影响奠定了基础。