TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity

• Verfasst von: Arlt, Elisabeth [VerfasserIn]
• Verfasst von: Tsvilovskyy, Volodymyr [VerfasserIn]
• Verfasst von: Freichel, Marc [VerfasserIn]
• Titel: TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity
• Verf.angabe: Elisabeth Arlt, Marco Fraticelli, Volodymyr Tsvilovskyy, Wiebke Nadolni, Andreas Breit, Thomas J. O’Neill, Stefanie Resenberger, Gunther Wennemuth, Christian Wahl-Schott, Martin Biel, Christian Grimm, Marc Freichel, Thomas Gudermann, Norbert Klugbauer, Ingrid Boekhoff, and Susanna Zierler
• E-Jahr: 2020
• Jahr: July 28, 2020
• Umfang: 11 S.
• Fussnoten: Published first July 13, 2020 ; Gesehen am 28.09.2020
• Titel Quelle: Enthalten in: National Academy of Sciences (Washington, DC)Proceedings of the National Academy of Sciences of the United States of America
• Ort Quelle: Washington, DC : National Acad. of Sciences, 1915
• Jahr Quelle: 2020
• Band/Heft Quelle: 117(2020), 30, Seite 18068-18078
• ISSN Quelle: 1091-6490
• DOI: doi:10.1073/pnas.1920122117
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1733881689

Abstract

<p>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.</p>