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.

Public Health Relevance

- In agreement with the mission of the NIH, this application advances fundamental knowledge required to make sound dietary recommendations on long chain n-3 polyunsaturated fatty acids and to translate the fatty acids into the clinic for targeting the immune system. The proposal is also relevant for public health because it aids in the development of a therapy for obese individuals, who display chronic inflammation and poor humoral immunity to viral infections.

National Institute of Health (NIH)
National Center for Complementary & Alternative Medicine (NCCAM)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Duffy, Linda C
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University of North Carolina Chapel Hill
Schools of Public Health
Chapel Hill
United States
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Guesdon, William; Kosaraju, Rasagna; Brophy, Patricia et al. (2018) Effects of fish oils on ex vivo B-cell responses of obese subjects upon BCR/TLR stimulation: a pilot study. J Nutr Biochem 53:72-80
Kilburg-Basnyat, Brita; Reece, Sky W; Crouch, Miranda J et al. (2018) Specialized Pro-Resolving Lipid Mediators Regulate Ozone-Induced Pulmonary and Systemic Inflammation. Toxicol Sci 163:466-477
Leng, Xiaoling; Kinnun, Jacob J; Cavazos, Andres T et al. (2018) All n-3 PUFA are not the same: MD simulations reveal differences in membrane organization for EPA, DHA and DPA. Biochim Biophys Acta Biomembr 1860:1125-1134
Torres, Maria J; Kew, Kim A; Ryan, Terence E et al. (2018) 17?-Estradiol Directly Lowers Mitochondrial Membrane Microviscosity and Improves Bioenergetic Function in Skeletal Muscle. Cell Metab 27:167-179.e7
Shaikh, Saame Raza; Shaver, Patti R; Shewchuk, Brian M (2018) High Fat Diet Dysregulates Hypothalamic-Pituitary Axis Gene Expression Levels which are Differentially Rescued by EPA and DHA Ethyl Esters. Mol Nutr Food Res 62:e1800219
Kinnun, Jacob J; Bittman, Robert; Shaikh, Saame Raza et al. (2018) DHA Modifies the Size and Composition of Raftlike Domains: A Solid-State 2H NMR Study. Biophys J 114:380-391
Sullivan, E Madison; Pennington, Edward Ross; Sparagna, Genevieve C et al. (2018) Docosahexaenoic acid lowers cardiac mitochondrial enzyme activity by replacing linoleic acid in the phospholipidome. J Biol Chem 293:466-483
Crouch, Miranda J; Kosaraju, Rasagna; Guesdon, William et al. (2018) Frontline Science: A reduction in DHA-derived mediators in male obesity contributes toward defects in select B cell subsets and circulating antibody. J Leukoc Biol :
Wassall, Stephen R; Leng, Xiaoling; Canner, Samuel W et al. (2018) Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation. Biochim Biophys Acta Biomembr 1860:1985-1993
Kosaraju, Rasagna; Guesdon, William; Crouch, Miranda J et al. (2017) B Cell Activity Is Impaired in Human and Mouse Obesity and Is Responsive to an Essential Fatty Acid upon Murine Influenza Infection. J Immunol 198:4738-4752

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