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（由应用提供）：N-3多不饱和脂肪酸（PUFA），eicosapentaenoic（EPA）和Docosahecahexaenoic（DHA）酸是具有临床应用的生物活性分子，用于抑制慢性感染。 N-3 PUFAS转化为诊所的主要障碍是对N-3 PUFA调节注射和此外的机制的有限理解，而N-3 PUFA对B细胞的免疫抑制作用的其他方面的后果，我们提出的是N-3 Pufas对Immunosepress的结果，并呈现了对Antigemen+ the Antigemen+ the AntigeN的结果。数据提出了令人兴奋的可能性，即N-3 PUFA可简单地抑制细胞介导的感染并增强精选疾病中的体液免疫组织化学。我们的研究计划的长期目标是确定N-3 PUFA对公众和特定临床人群的免疫组织化学的有效性。目前的目标是确定EPA和DHA在调节炎症细胞因子和肥胖小鼠中的炎症细胞因子和体液免疫组织化学中的个体和综合效率。关注肥胖症的理由是，肥胖个体除了慢性炎症外还显示出较差的体液免疫组织化学。中心假设是N-3 PUFA会产生CD4+ Th2细胞因子，从而增强B细胞活化和抗体的产生。我们还将通过靶向G蛋白偶联受体（GPR）120，N-3 PUFA传感器来增强N-3 PUFAS增强Th2细胞因子和B细胞活性的其他假设。 AIM 1将建立N-3 PUFA抑制Th1/Th17细胞因子并增强瘦小鼠的Th2细胞因子和Treg。然后，AIM 1将通过靶向免疫突触和选择细胞类型的GPR120来确定N-3 PUFA是否可以增强Th2细胞因子。 AIM 2将决定N-3 PUFA如何增强瘦小鼠的体液免疫学。 AIM 2首先将阐明升高的Th2细胞因子如何响应N-3 PUFA，从而增强B细胞活性。然后，AIM 2将剖析N-3 PUFA可以直接增强B细胞活性的其他机制的贡献。其中包括刺激B细胞GPR120信号传导的N-3 PUFA和生成促脂质脂质介体。 AIM 3将确定N-3 PUFA的效率在响应包括影响在内的几种抗原响应肥胖小鼠的抗体产生减少。 AIM 3还将通过以GPR120依赖性方式增强选定特定的B细胞来确定N-3 PUFAS在抑制注射方面的效率。该方法将依赖于免疫学测定，遗传小鼠模型，脂肪组学和生物物理成像方法。该提案很重要，因为它将定义EPA+DHA（建模非处方和处方补充剂）以及EPA和DHA在瘦肉和肥胖小鼠中注射和体液免疫的单个活动。这项研究具有创新性，因为它使用完整的方法来测试新的机制，以挑战N-3 PUFAS仅具有抑制或解决注入的实用性的一般范式。该项目的完成将为人类免疫的精选N-3 PUFA提供研究。