The succinate-GPR91 axis is involved in the regulation of mast cell response

[[abstract]]Background: Succinate, an intermediate of the TCA cycle in the mitochondria, has recently been shown to regulate various cellular functions through the G-protein-coupled, metabolic receptor, GPR91. But, its role in the regulation of innate immunity and mast cells, a critical cell type in mucosal and allergic responses, remain unclear. The objective of this study was, therefore, to investigate whether the succinate-GPR91 axis plays a role in regulating the mast cell response. Methods: Mouse bone marrow-derived mast cells (BMMCs) and human peripheral blood-derived cultured mast cells (HCMCs) were used as a model, and the effect of varying doses of succinate on IgE-mediated mast cell response was examined. Degranulation was measured by analyzing the level of b-hexosaminidase, and the levels of lipid mediator release and cytokine production were analyzed by ELISA. Flow cytometric analyses were performed to determine the expression of GPR91 and the level of intracellular calcium, while Western blotting was used to determine the level of ERK activation. Results: Flow cytometric analysis showed ?rst that mast cells expressed, constitutively, GPR91, and its level increased in activated mast cells. Signi?cantly, increased levels of degranulation, leukotriene C4 (LTC4) and IL-13 were noted in succinatetreated BMMCs and HCMCs following the IgE-mediated activation, concomitant with enhanced levels of intracellular calcium and phosphorylated ERK. Interestingly, succinate appeared to be able to inhibit the release of prostaglandin E2 (PGE2), which was in contrast to the increased level of LTC4, in activated mast cells, suggesting a differential impact of succinate on the generation of lipid mediators. Conclusions: These results suggest that the succinate-GPR91 axis is functional in regulating the responses of both human and mouse mast cells, supporting the existence of a novel receptor-ligand axis in controlling mast cell and hence the allergic response