Disrupted Lipid Raft Shuttling of FcεRI by n-3 Polyunsaturated Fatty Acid Is Associated With Ligation of G Protein-Coupled Receptor 120 (GPR120) in Human Mast Cell Line LAD2

Abstract

n-3 polyunsaturated fatty acids (PUFA) influences a variety of disease conditions, such as hypertension, heart disease, diabetes, cancer and allergic diseases, by modulating membrane constitution, inhibiting production of proinflammatory eicosanoids and cytokines, and binding to cell surface and nuclear receptors. We have previously shown that n-3 PUFA inhibit mast cell functions by disrupting high affinity IgE receptor (FcεRI) lipid raft partitioning and subsequent suppression of FcεRI signaling in mouse bone marrow-derived mast cells. However, it is still largely unknown how n-3 PUFA modulate human mast cell function, which could be attributed to multiple mechanisms. Using a human mast cell line (LAD2), we have shown similar modulating effects of n-3 PUFA on FcεRI lipid raft shuttling, FcεRI signaling, and mediator release after cell activation through FcεRI. We have further shown that these effects are at least partially associated with ligation of G protein-coupled receptor 120 expressed on LAD2 cells. This observation has advanced our mechanistic knowledge of n-3 PUFA's effect on mast cells and demonstrated the interplay between n-3 PUFA, lipid rafts, FcεRI, and G protein-coupled receptor 120. Future research in this direction may present new targets for nutritional intervention and therapeutic agents.

Quercetin and Resveratrol Differentially Decrease Expression of the High-Affinity IgE Receptor (FcεRI) by Human and Mouse Mast Cells

“…Hence, it is also possible that the presence of high concentrations of IgE during phytochemical treatment stabilizes FcεRI expression and thus, we do not see an effect on SYK phosphorylation ( Figure 4 A and Figure 6 A) or BMMC degranulation ( Figure 4 C). Certainly, IgE has been shown to stabilize FcεRI on the cell surface [ 62 ] and increase its localization to the cell membrane over time [ 42 , 63 ]. For TNF production, though upstream signaling pathways do not seem to be inhibited after FcεRI activation, it is also possible that longer term changes to the expression and activation of signaling pathway components downstream of SYK and ERK were still sufficient to affect TNF production.…”

Effects of Dietary Components on Mast Cells: Possible Use as Nutraceuticals for Allergies?

“…EPA and DHA, which can be synthesized in the body from ALA, reduced the release of β-hex (≈25%) and cysteinyl-leukotriene (cys-LT) (≈80%) by LAD2 cells [34]. EPA and DHA thereby reduced the localization of the high affinity IgE receptor FcεRI in lipid rafts and decreased the phosphorylation of Lyn, spleen tyrosine kinase (Syk), and linker for activation of T cells (LAT) signaling molecules in IgE/antigen-stimulated LAD2 cells.…”

“…EPA and DHA may bind to and activate GPR120 in MC, potentially leading to increased cyclic adenosine monophosphate levels and the activation of protein kinase A, which could suppress MC degranulation [34]. Furthermore, ALA, EPA, and DHA inhibited the production of Th2-associated cytokines IL-4, IL-5, and IL-13 in activated BMMC and MC/9 by suppressing the nuclear expression of the transcription factors GATA binding protein (GATA) 1 and 2 [35].…”