TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity

• DOI: 10.1073/pnas.1920122117
• Publication Date: 2020-07-14T00:31:55Z
• Authors: Elisabeth Arlt; Marco Fraticelli; Volodymyr Tsvilov...; Wiebke Nadolni; Andreas Breit; Thomas J. O’Neill; Stefanie Resenberger; Gunther Wennemuth; Christian Wahl-Sc...; Martin Biel; Christian Grimm; Marc Freichel; Thomas Gudermann; Norbert Klugbauer; Ingrid Boekhoff; Susanna Zierler
• Keywords: Ex vivo

Significance The worldwide prevalence of allergic and anaphylactic reactions has increased massively over recent decades. Mast cells basophils are essential drivers these diseases, releasing inflammatory mediators such as histamine. Here, we link the endolysosomal two-pore channel TPC1 to systemic anaphylaxis in vivo underlying mast cell function ex vivo. TPC1-deficient mice develop enhanced reflected by a drop body temperature slower recovery compared wild-type animals. Genetic deletion or pharmacological inhibition enhances degranulation histamine release due accelerated calcium release, mainly from endoplasmic reticulum. Accordingly, it is tempting speculate that activation ameliorates degranulation, highlighting potential drug target against hypersensitivity.