Fish oil has immunosuppressive properties that could provide treatment for numerous inflammatory and autoimmune disorders. The primary bioactive components of fish oil, which are the n-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can exert differential effects on many cell types in the body. A major limitation in the development of fish oil as a therapeutic is the lack of mechanistic understanding of how fish oil exerts its functional effects. One emerging mechanism is that EPA and DHA have unique biophysical properties that could disrupt the lateral organization of plasma membrane lipids and proteins critical for signaling and cell-cell communication, such as lipid rafts and the immunological synapse. In this study, we investigate a potential mechanism for this disruption in B cells, a cell type poorly represented in the field of n-3 PUFA research. The central hypothesis for this study was that fish oil disrupts lateral organization of lipid rafts and suppresses downstream B cell function. Using high and low fat fish oil diets in mice, we demonstrated that fish oil dispersed clustering of B cell lipid rafts on a micron scale, and enhanced membrane molecular order upon cross-linking raft domains. We found that the effects on lipid rafts are primarily driven by DHA and not EPA, and that n-3 PUFAs have a limited influence on non-raft lateral organization. Finally, we show that fish oil suppresses B cell antigen presentation and subsequent CD4+ T cell IL-2 secretion, by disrupting the B cell side of the immunological synapse. Taken together, this work highlights the utility of fish oil, more specifically DHA, as a tool for disrupting plasma membrane lateral organization. We add to the biochemical understanding of how these fatty acids may disrupt various downstream signaling events and cell-cell interactions. It also emphasizes the importance of the plasma membrane as a target for suppressing other cellular functions mediated through lipid raft domains. Finally, these studies add B cells as key targets for suppression of antigen presentation in diseases such as autoimmune disorders.
|Advisor:||Shaikh, Saame Raza|
|Commitee:||Bridges, Lance C., Chalovich, Joseph M., Muller-Borer, Barbara J.|
|School:||East Carolina University|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Subjects:||Cellular biology, Biochemistry|
|Keywords:||B cells, Fish oil, Immunological synapse, Lipid rafts, Plasma membrane|
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