K2.1 (TREK1), a two-pore domain potassium channel, has emerged as regulator of leukocyte transmigration into the central nervous system. In the context of skeletal muscle, immune cell infiltration constitutes the pathogenic hallmark of idiopathic inflammatory myopathies (IIMs). However, the underlying mechanisms remain to be elucidated. In this study, we investigated the role of K2.1 in the autoimmune response of IIMs. We detected K2.1 expression in primary skeletal muscle and endothelial cells of murine and human origin. We observed an increased pro-inflammatory cell response, adhesion and transmigration by pharmacological blockade or genetic deletion of K2.1 and in myositis mouse models. Of note, our findings were not restricted to endothelial cells as skeletal muscle cells with impaired K2.1 function also demonstrated a strong pro-inflammatory response. Conversely, these features were abrogated by activation of K2.1 and improved the disease course of a myositis mouse model. In humans, K2.1 expression was diminished in IIM patients compared to non-diseased controls arguing for the translatability of our findings. In summary, K2.1 may regulate the inflammatory response of skeletal muscle. Further research is required to understand whether K2.1 could serve as novel therapeutic target.

中文翻译：

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K2P2.1 是特发性炎症性肌病炎症细胞反应的调节因子


K2.1 (TREK1) 是一种双孔域钾通道，已成为白细胞迁移至中枢神经系统的调节剂。在骨骼肌中，免疫细胞浸润构成了特发性炎症性肌病 (IIM) 的致病标志。然而，潜在的机制仍有待阐明。在本研究中，我们研究了 K2.1 在 IIM 自身免疫反应中的作用。我们在小鼠和人类来源的原代骨骼肌和内皮细胞中检测到 K2.1 表达。我们在肌炎小鼠模型中观察到，通过药物阻断或 K2.1 基因删除，促炎细胞反应、粘附和迁移增加。值得注意的是，我们的研究结果不仅限于内皮细胞，K2.1 功能受损的骨骼肌细胞也表现出强烈的促炎症反应。相反，K2.1 的激活消除了这些特征，并改善了肌炎小鼠模型的病程。在人类中，与未患病对照相比，IIM 患者的 K2.1 表达减少，这证明了我们的研究结果的可转化性。综上所述，K2.1可能调节骨骼肌的炎症反应。需要进一步的研究来了解 K2.1 是否可以作为新的治疗靶点。