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: 9031050
• 负责人: SAAME R SHAIKH
• 金额: $ 33万
• 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 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031050
• 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）是具有抑制慢性炎症临床应用的生物活性分子。将n-3 PUFAs转化为临床的主要障碍是对n-3 PUFAs调节炎症的机制以及n-3 PUFAs对免疫系统其他方面的影响的理解有限。我们已经发现n-3 PUFA增强来自B细胞的鼠免疫应答，我们提出这是n-3 PUFA对抗原呈递细胞和CD 4 + 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选定疾病的体液免疫。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免疫力的疗效。目前的目标是确定EPA和DHA在调节瘦小鼠和肥胖小鼠的炎性细胞因子和体液免疫中的单独和组合功效。关注肥胖的基本原理是，肥胖个体除了慢性炎症外，还表现出体液免疫力低下。核心假设是n-3 PUFA产生促进B细胞活化和抗体产生的CD 4 + Th 2细胞因子。我们还将测试另外的假设，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）增强Th 2细胞因子和B细胞活性。目的1建立n-3多不饱和脂肪酸抑制Th 1/Th 17型细胞因子和提高Th 2型细胞因子和T淋巴细胞的瘦小鼠模型。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GPR 120来增强Th 2细胞因子。目的2研究n-3多不饱和脂肪酸对瘦小鼠体液免疫功能的增强作用。目的2将首先阐明升高的Th 2细胞因子如何响应于n-3 PUFA而增强B细胞活性。目的2将剖析n-3 PUFA可直接增强B细胞活性的其他机制的贡献。这些包括刺激B细胞GPR 120信号传导和产生促分解脂质介质的n-3 PUFA。目的3将确定n-3 PUFAs在挽救肥胖小鼠响应于包括流感在内的几种抗原的抗体产生减少中的功效。目的3还将通过以GPR 120依赖性方式增强选择的脂肪特异性B细胞来确定n-3 PUFA抑制炎症的功效。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（建模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，因为它使用互补方法测试了新的机制，以挑战n-3 PUFA仅用于抑制或解决炎症的一般范式。该项目的完成将为选择n-3 PUFA对人体免疫力的研究奠定基础。