Aloe-emodin, a naturally occurring anthraquinone, is a highly potent mast cell stabilizer through activating mitochondrial calcium uniporter

Mast cells play a fundamental role in immune system. Upon stimulation, they are activated via IgE dependent or independent pathway and then release granules which contain plenty of preformed constituents. Mast cell stabilizers are commonly used clinically for inhibiting the degranulation of mast cells. In the current study, we firstly identified aloe-emodin, a naturally occurring anthraquinone, was a prominent mast cell stabilizer. It could strikingly dampen IgE/FcεRI- and MAS-related G protein coupled receptor (Mrgpr)-mediated mast cell degranulation in vitro and in vivo. Mechanism study indicated that aloe-emodin rapidly and reversibly decreased cytosolic CA²⁺ (CA²⁺_[c]) concentration through enhancing the mitochondrial CA²⁺ (CA²⁺_[m]) uptake. After genetically silencing or pharmacologic inhibiting mitochondrial calcium uniporter (MCU), the effects of aloe-emodin on the CA²⁺_[c] level and mast cell degranulation were significantly weakened. In contrast to six clinical drugs with mast cell stabilizing properties (amlexanox, tranilast, ketotifen, cromolyn disodium salt, dexamethasone and pimecrolimus), aloe-emodin showed an impressive and potent inhibitory action on the mast cell degranulation. Collectively, aloe-emodin is a highly potent mast cell stabilizer. By directly activating MCU, it decreases CA²⁺_[c] level to suppress mast cell degranulation. Our study may provide a promising candidate for the treatment of mast cell activation-related diseases.