Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction.

Abstract

BackgroundSUCNR1 is a sensor of extracellular succinate, a Krebs cycle intermediate generated in excess during oxidative stress and has been linked to metabolic regulation and inflammation. While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated.MethodsCord blood‐derived mast cells and human mast cell line LAD‐2 challenged by SUCNR1 ligands were analyzed for the activation and mediator release. Effects on mast cell‐dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti‐IgE, respectively.ResultsSUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non‐metabolite agonist cis‐epoxysuccinate, renders mast cells hypersensitive to IgE‐dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate‐potentiated mast cell reactivity was attenuated by SUCNR1 knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal‐regulated kinase. Both succinate and cis‐epoxysuccinate dose‐dependently potentiated antigen‐induced contraction in a mast cell‐dependent guinea pig airway model, associated with increased generation of cysteinyl‐leukotrienes and histamine in trachea. Similarly, cis‐epoxysuccinate aggravated IgE‐receptor‐induced contraction of human bronchi, which was blocked by SUCNR1 antagonism.ConclusionSUCNR1 amplifies IgE‐receptor‐induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell‐dependent inflammation.