TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity

Abstract

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.

Deciphering the Role of Endolysosomal Ca2+ Channels in Immunity

“…The study also found that TPC1 modulation either by genetic deletion or by pharmacological inhibition by trans -Ned-19 augmented mastocyte degranulation and evoked the release of inflammatory mediator (histamine) from mast cells ( 9 ), which are tissue-resident cells of the immune system that play a role in inflammatory and allergic reactions. The number and the size of the mastocytes were significantly attenuated in the TPC1-deficient murine model compared to WT controls ( 9 ). The cellular mechanisms underlying the regulation of TPC1-mediated endolysosomal Ca 2+ signals in the development of inflammatory and allergic reactions warrants further investigation to aid the development of new drugs for the treatment of anaphylaxis and allergic hypersensitivity.…”

“…In the in vivo TPC1KO murine model, systemic anaphylaxis was exaggerated, manifested by a profound drop in body temperature compared to WT mice ( 9 ). The study also found that TPC1 modulation either by genetic deletion or by pharmacological inhibition by trans -Ned-19 augmented mastocyte degranulation and evoked the release of inflammatory mediator (histamine) from mast cells ( 9 ), which are tissue-resident cells of the immune system that play a role in inflammatory and allergic reactions. The number and the size of the mastocytes were significantly attenuated in the TPC1-deficient murine model compared to WT controls ( 9 ).…”

“…They found that NAADP-mediated Ca 2+ release is a significant pathway that drives T cell cytolytic granule exocytosis (15). Recently, Elisabeth et al (2020) reported for the first time that endolysosomal Ca 2+ signals via TPC1 mediate the development of the immune response by triggering the release of inflammatory mediators in a mechanism involving Ca 2+ cross talk between TPC1-mediated and endoplasmic reticulum (ER) Ca 2+ stores (9). In the in vivo TPC1KO murine model, systemic anaphylaxis was exaggerated, manifested by a profound drop in body temperature compared to WT mice (9).…”

“…Recently, Elisabeth et al (2020) reported for the first time that endolysosomal Ca 2+ signals via TPC1 mediate the development of the immune response by triggering the release of inflammatory mediators in a mechanism involving Ca 2+ cross talk between TPC1-mediated and endoplasmic reticulum (ER) Ca 2+ stores (9). In the in vivo TPC1KO murine model, systemic anaphylaxis was exaggerated, manifested by a profound drop in body temperature compared to WT mice (9). The study also found that TPC1 modulation either by genetic deletion or by pharmacological inhibition by trans-Ned-19 augmented mastocyte degranulation and evoked the release of inflammatory mediator (histamine) from mast cells (9), which are tissue-resident cells of the immune system that play a role in inflammatory and allergic reactions.…”

“…TRPML2 is an endolysosomal Ca 2+ channel that has been shown to have direct roles in the release of chemokine/cytokine ( 8 ). Additionally, TPC1 is an endolysosomal Ca 2+ channel that has been reported to be involved in the development of the immune response and the release of inflammatory mediators ( 9 ). Although it has become clear that endolysosomal Ca 2+ signals play pivotal roles in health and disease, the complex dynamics underlying the regulation of Ca 2+ signalling via endolysosomal channels and the involvement of these in physiological processes related to immunity have remained elusive.…”