LAUSR

Significance The worldwide prevalence of allergic and anaphylactic reactions has increased massively over recent decades. Mast cells and basophils are essential drivers of these diseases, releasing inflammatory mediators such as histamine. Here, we link the endolysosomal two-pore channel TPC1 to systemic anaphylaxis in vivo and underlying mast cell function ex vivo. TPC1-deficient mice develop enhanced systemic anaphylaxis reflected by a drop in body temperature and slower recovery compared to wild-type animals. Genetic deletion or pharmacological inhibition of TPC1 enhances mast cell degranulation and histamine release due to accelerated calcium release, mainly from the endoplasmic reticulum. Accordingly, it is tempting to speculate that activation of TPC1 ameliorates mast cell degranulation, highlighting TPC1 as a potential drug target against allergic hypersensitivity. Mast cells and basophils are main drivers of allergic reactions and anaphylaxis, for which prevalence is rapidly increasing. Activation of these cells leads to a tightly controlled release of inflammatory mediators stored in secretory granules. The release of these granules is dependent on intracellular calcium (Ca2+) signals. Ca2+ release from endolysosomal compartments is mediated via intracellular cation channels, such as two-pore channel (TPC) proteins. Here, we uncover a mechanism for how TPC1 regulates Ca2+ homeostasis and exocytosis in mast cells in vivo and ex vivo. Notably, in vivo TPC1 deficiency in mice leads to enhanced passive systemic anaphylaxis, reflected by increased drop in body temperature, most likely due to accelerated histamine-induced vasodilation. Ex vivo, mast cell-mediated histamine release and degranulation was augmented upon TPC1 inhibition, although mast cell numbers and size were diminished. Our results indicate an essential role of TPC1 in endolysosomal Ca2+ uptake and filling of endoplasmic reticulum Ca2+ stores, thereby regulating exocytosis in mast cells. Thus, pharmacological modulation of TPC1 might blaze a trail to develop new drugs against mast cell-related diseases, including allergic hypersensitivity.