TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity
TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity
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DOI：
10.1073/pnas.1920122117
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发表时间：
2020-07-28
影响因子：
11.1
通讯作者：
Zierler, Susanna
中科院分区：
文献类型：
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作者：
Arlt, Elisabeth;Fraticelli, Marco;Zierler, Susanna
肥大细胞和嗜碱性细胞是过敏反应和过敏反应的主要驱动因素，其患病率正在迅速增加。这些细胞的激活导致储存在分泌颗粒中的炎症介质的严格控制释放。这些颗粒的释放依赖于细胞内钙（Ca2+）信号。Ca2+释放从内溶酶体室室介导通过细胞内阳离子通道，如双孔通道（TPC）蛋白。在这里，我们揭示了TPC1在体内和离体肥大细胞中如何调节Ca2+稳态和胞吐的机制。值得注意的是，小鼠体内TPC1缺乏会导致被动全身性过敏反应增强，表现为体温下降加剧，这很可能是由于组胺诱导的血管舒张加速。在体外，抑制TPC1后，肥大细胞介导的组胺释放和脱颗粒增强，尽管肥大细胞的数量和大小减少。我们的研究结果表明，TPC1在内溶酶体Ca2+摄取和内质网Ca2+储存的填充中起重要作用，从而调节肥大细胞的胞吐。因此，TPC1的药理学调节可能为开发治疗肥大细胞相关疾病（包括过敏性超敏反应）的新药开辟一条道路。
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 intra-cellular cation channels, such as two-pore channel (TPC) proteins. Here, we uncover a mechanism for how TPC1 regulates Ca2+ ho-meostasis 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 re-ticulum 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.