The formation of neutrophil extracellular traps (NETs) is a process releasing into the extracellular space networks of chromatin fibers decorated with granular proteins. It is implicated in infection-related as well as sterile inflammation. Monosodium urate (MSU) crystals serve as damage-associated molecular pattern (DAMP) in various conditions of disease. Formation of NETs or aggregated NETs (aggNETs) orchestrates initiation and resolution of MSU crystals-triggered inflammation, respectively. Elevated intracellular calcium levels and the generation of reactive oxygen species (ROS) are crucial for the formation of MSU crystal-induced NETs. However, the exact signaling pathways involved are still elusive. Herein, we demonstrate that the ROS-sensing, non-selective calcium-permeable channel transient receptor potential cation channel subfamily M member 2 (TRPM2) is required for a full-blown MSU crystal-induced NET formation. Primary neutrophils from TRPM2−/− mice showed reduced calcium influx and ROS production and, consequently a reduced formation of MSU crystal-induced NETs and aggNETs. Furthermore, in TRPM2−/− mice the infiltration of inflammatory cells into infected tissues and their production of inflammatory mediators was suppressed. Taken together these results describe an inflammatory role of TRPM2 for neutrophil-driven inflammation and identify TRPM2 as potential target for therapeutic intervention.

中文翻译：

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瞬时受体电位 melastatin 2 调节中性粒细胞胞外陷阱的形成并延迟中性粒细胞驱动的无菌炎症的消退

中性粒细胞胞外陷阱 (NETs) 的形成是一个过程，它释放到装饰有颗粒蛋白的染色质纤维的胞外空间网络中。它与感染相关以及无菌性炎症有关。尿酸单钠 (MSU) 晶体在各种疾病条件下充当损伤相关分子模式 (DAMP)。NET 或聚合 NET (aggNET) 的形成分别协调了 MSU 晶体引发的炎症的启动和消退。细胞内钙水平升高和活性氧 (ROS) 的产生对于 MSU 晶体诱导的 NET 的形成至关重要。然而，所涉及的确切信号通路仍然难以捉摸。在这里，我们证明了 ROS 感应，非选择性钙渗透通道瞬时受体电位阳离子通道亚家族 M 成员 2 (TRPM2) 是成熟的 MSU 晶体诱导的 NET 形成所必需的。来自 TRPM2−/− 小鼠的原代中性粒细胞显示钙流入和 ROS 产生减少，因此 MSU 晶体诱导的 NET 和 aggNET 的形成减少。此外，在 TRPM2-/- 小鼠中，炎症细胞向受感染组织的浸润及其炎症介质的产生受到抑制。综上所述，这些结果描述了 TRPM2 对中性粒细胞驱动的炎症的炎症作用，并将 TRPM2 确定为治疗干预的潜在靶点。因此减少了 MSU 晶体诱导的 NET 和 aggNET 的形成。此外，在 TRPM2-/- 小鼠中，炎症细胞向受感染组织的浸润及其炎症介质的产生受到抑制。综上所述，这些结果描述了 TRPM2 对中性粒细胞驱动的炎症的炎症作用，并将 TRPM2 确定为治疗干预的潜在靶点。因此减少了 MSU 晶体诱导的 NET 和 aggNET 的形成。此外，在 TRPM2-/- 小鼠中，炎症细胞向受感染组织的浸润及其炎症介质的产生受到抑制。综上所述，这些结果描述了 TRPM2 对中性粒细胞驱动的炎症的炎症作用，并将 TRPM2 确定为治疗干预的潜在靶点。