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

基本信息

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
项目类别：
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

项目摘要

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.