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: 9488876
• 负责人: SAAME R SHAIKH
• 金额: --
• 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 2017-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9488876
• 关键词: Adipose tissue; Agreement; Anti-Inflammatory Agents; Anti-inflammatory; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocytes; Biophysics; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Chronic; Clinic; Clinical; Complementary and alternative medicine; Data; Development; Diet; Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Equilibrium; Esters; Fatty Acids; Fish Oils; Foundations; G-Protein-Coupled Receptors; General Population; Genetic; Goals; Human; Humoral Immunities; Immune Targeting; Immune response; Immune system; Immunity; Immunology procedure; Immunosuppression; Individual; Inflammation; Inflammatory; Influenza; Interleukin-10; Knowledge; Mediating; Membrane; Mission; Modality; Modeling; Molecular; Mus; N-3 polyunsaturated fatty acid; Obese Mice; Obesity; Phenotype; Population; Proteins; Public Health; Recommendation; Regulatory T-Lymphocyte; Research; Signal Transduction; Supplementation; Testing; Th2 Cells; Thinness; Translating; Translations; Triglycerides; United States National Institutes of Health; Viral Tumor Antigens; Virus Diseases; cell type; clinical application; cytokine; imaging modality; immunological synapse; in vivo; innovation; lipid mediator; mouse model; murine antibody; novel; programs; public health relevance; 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（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，具有临床应用用于抑制慢性炎症。将 n-3 PUFA 转化为临床的一个主要障碍是对 n-3 PUFA 调节炎症的机制以及 n-3 PUFA 对免疫系统其他方面的影响的了解有限。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。这些数据提出了令人兴奋的可能性，即 n-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 对普通公众和特定临床人群的免疫力的功效。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单独和联合功效。关注肥胖的理由是，肥胖者除了慢性炎症外，还表现出体液免疫能力差。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。我们还将测试另一个假设，即 n-3 PUFA 通过靶向 G 蛋白偶联受体 (GPR) 120（一种 n-3 PUFA 传感器）来增强 Th2 细胞因子和 B 细胞活性。目标 1 将在瘦小鼠中建立 n-3 PUFA 抑制 Th1/Th17 细胞因子并增强 Th2 细胞因子和 Tregs。然后，目标 1 将确定 n-3 PUFA 是否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 如何增强瘦小鼠的体液免疫力。目标 2 将首先阐明升高的 Th2 细胞因子如何响应 n-3 PUFA 增强 B 细胞活性。然后，目标 2 将剖析 n-3 PUFA 直接增强 B 细胞活性的其他机制的贡献。其中包括刺激 B 细胞 GPR120 信号传导并产生促溶解脂质介质的 n-3 PUFA。目标 3 将确定 n-3 PUFA 在挽救肥胖小鼠针对包括流感在内的多种抗原的抗体产生减少方面的功效。目标 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 在抑制炎症方面的功效。该方法将依赖于免疫学测定、遗传小鼠模型、脂质组学和生物物理成像方法。该提案意义重大，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 对瘦小鼠和肥胖小鼠的炎症和体液免疫的个体活性。这项研究具有创新性，因为它使用补充方法测试了新颖的机制，挑战了 n-3 PUFA 仅具有抑制或解决炎症作用的一般范式。该项目的完成将为研究选定的 n-3 PUFA 对人类免疫力的影响奠定基础。