Suppressing inflammation and boosting humoral immunity with n-3 PUFAs

 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)，是临床上应用于抑制慢性炎症的生物活性分子。将n-3多不饱和脂肪酸转化到临床的一个主要障碍是对n-3多不饱和脂肪酸调节炎症的机制以及n-3多不饱和脂肪酸对免疫系统其他方面的影响的有限了解。我们发现n-3PUFAs能增强小鼠B细胞的免疫应答，我们认为这是由于n-3PUFAs对抗原提呈细胞和CD4+T细胞的免疫抑制作用所致。这些数据提高了令人兴奋的可能性，即n-3多不饱和脂肪酸可用于在选定的疾病中同时抑制细胞介导的炎症和增强体液免疫。我们研究计划的长期目标是确定n-3多不饱和脂肪酸对普通公众和特定临床人群的免疫效果。目前的目标是确定EPA和DHA在调节瘦小和肥胖小鼠的炎性细胞因子和体液免疫方面的单独和联合疗效。关注肥胖的理由是，除了慢性炎症外，肥胖个体还表现出较低的体液免疫力。中心假说是n-3多不饱和脂肪酸产生CD4+Th2细胞因子，促进B细胞的激活和抗体的产生。我们还将测试额外的假设，即n-3PUFA通过靶向N-3PUFA传感器G蛋白偶联受体(GPR)120来增强Th2细胞因子和B细胞活性。目的1在瘦小鼠体内建立n-3多不饱和脂肪酸，抑制Th1/Th17细胞因子，增强Th2细胞因子和Tregs。然后，目标1将确定n-3多不饱和脂肪酸是否通过靶向特定细胞类型的免疫突触和GPR120来促进Th2细胞因子。目的2将确定n-3多不饱和脂肪酸如何提高瘦小鼠的体液免疫。目的2将首先阐明升高的Th2细胞因子是如何响应n-3PUFAs而增强B细胞活性的。目标2随后将剖析n-3多不饱和脂肪酸可直接增强B细胞活性的其他机制的贡献。这些包括n-3多不饱和脂肪酸刺激B细胞GPR120信号和产生促进分解的脂质介质。目的3确定n-3多不饱和脂肪酸在挽救肥胖小鼠对包括流感在内的几种抗原反应的抗体产生减少方面的有效性。目的3还将确定n-3多不饱和脂肪酸通过以GPR120依赖的方式增强选定的脂肪特异性B细胞而抑制炎症的疗效。该方法将依赖于免疫学分析、遗传小鼠模型、脂质组学和生物物理成像方法。这项建议意义重大，因为它将定义EPA+DHA(模拟非处方药和处方药补充剂)的功效，以及EPA和DHA对瘦小和肥胖小鼠炎症和体液免疫的单独作用。这项研究具有创新性，因为它使用互补的方法来测试新的机制，以挑战n-3多不饱和脂肪酸只对抑制或化解炎症有用的一般范式。该项目的完成将为使用精选的n-3多不饱和脂肪酸对人体免疫的研究提供基础。

 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.