Despite numerous biomarkers being proposed for rheumatoid arthritis (RA), a gap remains in our understanding of their mechanisms of action. In this study, we discovered a novel role for gelsolin (GSN), an actin-binding protein whose levels are notably reduced in the plasma of RA patients. We elucidated that GSN is a key regulator of NLRP3 inflammasome activation in macrophages, providing a plausible explanation for the decreased secretion of GSN in RA patients. We found that GSN interacts with NLRP3 in LPS-primed macrophages, hence modulating the formation of the NLRP3 inflammasome complex. Reducing GSN expression significantly enhanced NLRP3 inflammasome activation. GSN impeded NLRP3 translocation to the mitochondria; it contributed to the maintenance of intracellular calcium equilibrium and mitochondrial stability. This maintenance is crucial for controlling the inflammatory response associated with RA. Furthermore, the exacerbation of arthritic symptoms in GSN-deficient mice indicates the potential of GSN as both a diagnostic biomarker and a therapeutic target. Moreover, not limited to RA models, GSN has demonstrated a protective function in diverse disease models associated with the NLRP3 inflammasome. Myeloid cell-specific GSN-knockout mice exhibited aggravated inflammatory responses in models of MSU-induced peritonitis, folic acid-induced acute tubular necrosis, and LPS-induced sepsis. These findings suggest novel therapeutic approaches that modulate GSN activity, offering promise for more effective management of RA and a broader spectrum of inflammatory conditions.

尽管提出了许多用于类风湿性关节炎（RA）的生物标志物，但我们对其作用机制的理解仍然存在差距。在这项研究中，我们发现了凝溶胶蛋白 (GSN) 的新作用，这是一种肌动蛋白结合蛋白，其水平在 RA 患者血浆中显着降低。我们阐明 GSN 是巨噬细胞中 NLRP3 炎症小体激活的关键调节因子，为 RA 患者 GSN 分泌减少提供了合理的解释。我们发现 GSN 与 LPS 引发的巨噬细胞中的 NLRP3 相互作用，从而调节 NLRP3 炎性体复合物的形成。减少 GSN 表达显着增强 NLRP3 炎性体激活。 GSN 阻止 NLRP3 易位至线粒体；它有助于维持细胞内钙平衡和线粒体稳定性。这种维持对于控制与 RA 相关的炎症反应至关重要。此外，GSN 缺陷小鼠的关节炎症状恶化表明 GSN 作为诊断生物标志物和治疗靶点的潜力。此外，不仅限于 RA 模型，GSN 在与 NLRP3 炎性体相关的多种疾病模型中也表现出保护功能。骨髓细胞特异性 GSN 敲除小鼠在 MSU 诱导的腹膜炎、叶酸诱导的急性肾小管坏死和 LPS 诱导的败血症模型中表现出加重的炎症反应。这些发现提出了调节 GSN 活性的新治疗方法，为更有效地治疗 RA 和更广泛的炎症性疾病提供了希望。