The presence of gallstones (cholelithiasis) is a highly prevalent and severe disease and one of the leading causes of hospital admissions worldwide. Due to its substantial health impact, we investigated the biological mechanisms that lead to the formation and growth of gallstones. We show that gallstone assembly essentially requires neutrophil extracellular traps (NETs). We found consistent evidence for the presence of NETs in human and murine gallstones and describe an immune-mediated process requiring activation of the innate immune system for the formation and growth of gallstones. Targeting NET formation via inhibition of peptidyl arginine deiminase type 4 or abrogation of reactive oxygen species (ROS) production, as well as damping of neutrophils by metoprolol, effectively inhibit gallstone formation in vivo. Our results show that after the physicochemical process of crystal formation, NETs foster their assembly into larger aggregates and finally gallstones. These insights provide a feasible therapeutic concept to prevent cholelithiasis in patients at risk.

中文翻译：

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中性粒细胞胞外陷阱开始形成胆结石。

胆结石（胆石症）的存在是高度流行和严重的疾病，并且是全世界住院的主要原因之一。由于其对健康的重大影响，我们研究了导致胆结石形成和生长的生物学机制。我们显示胆结石组装实质上需要嗜中性白细胞胞外陷阱（NETs）。我们找到了在人和鼠胆结石中存在NET的一致证据，并描述了一种免疫介导的过程，该过程需要激活先天免疫系统来激活胆结石的形成和生长。通过抑制4型肽基精氨酸脱亚氨酶或消除活性氧（ROS）产生以及通过美托洛尔抑制嗜中性粒细胞来靶向形成NET，可有效抑制体内胆结石的形成。我们的结果表明，在晶体形成的物理化学过程之后，NET促进了它们组装成更大的聚集体，最后形成了胆结石。这些见解为预防高危患者的胆石症提供了可行的治疗方案。