The interplay between thrombosis and inflammation, termed thrombo-inflammation, causes acute organ damage in diseases such as ischaemic stroke and venous thrombosis. We have recently identified tetraspanin Tspan18 as a novel regulator of thrombo-inflammation. The tetraspanins are a family of 33 membrane proteins in humans that regulate the trafficking, clustering, and membrane diffusion of specific partner proteins. Tspan18 partners with the store-operated Ca²⁺ entry channel Orai1 on endothelial cells. Orai1 appears to be expressed in all cells and is critical in health and disease. Orai1 mutations cause human immunodeficiency, resulting in chronic and often lethal infections, while Orai1-knockout mice die at around the time of birth. Orai1 is a promising drug target in autoimmune and inflammatory diseases, and Orai1 inhibitors are in clinical trials. The focus of this review is our work on Tspan18 and Orai1 in Tspan18-knockout mice and Tspan18-knockdown primary human endothelial cells. Orai1 trafficking to the cell surface is partially impaired in the absence of Tspan18, resulting in impaired Ca²⁺ signaling and impaired release of the thrombo-inflammatory mediator von Willebrand factor following endothelial stimulation. As a consequence, Tspan18-knockout mice are protected in ischemia–reperfusion and deep vein thrombosis models. We provide new evidence that Tspan18 is relatively highly expressed in endothelial cells, through the analysis of publicly available single-cell transcriptomic data. We also present new data, showing that Tspan18 is required for normal Ca²⁺ signaling in platelets, but the functional consequences are subtle and restricted to mildly defective platelet aggregation and spreading induced by the platelet collagen receptor GPVI. Finally, we generate structural models of human Tspan18 and Orai1 and hypothesize that Tspan18 regulates Orai1 Ca²⁺ channel function at the cell surface by promoting its clustering.

中文翻译：

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Tspan18 是一种新型的血栓炎症调节剂。

血栓形成和炎症之间的相互作用（称为血栓炎症）会导致缺血性中风和静脉血栓形成等疾病的急性器官损伤。我们最近发现四跨膜蛋白 Tspan18 是血栓炎症的新型调节剂。四跨膜蛋白是人类体内 33 种膜蛋白的家族，调节特定伴侣蛋白的运输、聚集和膜扩散。Tspan18 与内皮细胞上商店操纵的 Ca ²⁺进入通道 Orai1 合作。Orai1 似乎在所有细胞中表达，对健康和疾病至关重要。Orai1 突变会导致人类免疫缺陷，导致慢性且往往致命的感染，而 Orai1 基因敲除的小鼠在出生时就会死亡。Orai1是治疗自身免疫和炎症性疾病的一个有前景的药物靶点，Orai1抑制剂正处于临床试验阶段。本综述的重点是我们在 Tspan18 敲除小鼠和 Tspan18 敲除原代人内皮细胞中对 Tspan18 和 Orai1 的研究。在 Tspan18 缺失的情况下，Orai1 向细胞表面的运输会部分受损，从而导致 Ca ²⁺信号传导受损以及内皮刺激后血栓炎症介质冯维勒布兰德因子的释放受损。因此，Tspan18 敲除小鼠在缺血再灌注和深静脉血栓形成模型中受到保护。通过对公开的单细胞转录组数据的分析，我们提供了新的证据表明 Tspan18 在内皮细胞中表达相对较高。我们还提供了新数据，表明 Tspan18 是血小板中正常 Ca ^{2+信号传导所必需的，但其功能后果很微妙，仅限于由血小板胶原受体 GPVI 诱导的轻度缺陷的血小板聚集和扩散。}最后，我们生成了人类 Tspan18 和 Orai1 的结构模型，并假设 Tspan18通过促进其聚集来调节细胞表面的Orai1 Ca ^{2+通道功能。}