Lee Jiyeon, Sasaki Fumiyuki, Koike Eri, Cho Minjeong, Lee Yeongun, Dho So Hee, Lee Jina, Lee Eunji, Toyohara Eri, Sunakawa Mika, Ishibashi Mariko, Hung Huynh Hiep, Nishioka Saki, Komine Ritsuko, Okura Chiaki, Shimizu Masumi, Ikawa Masahito, Yoshimura Akihiko, Morita Rimpei, Kim Lark Kyun
Department of Biomedical Sciences, Graduate School of Medical Science, Brain Korea 21 Project, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Microbiology and Immunology, Nippon Medical School, Tokyo, Japan.
Cell Death Differ. 2024 Dec;31(12):1679-1694. doi: 10.1038/s41418-024-01367-6. Epub 2024 Aug 24.
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.
尽管已经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存在差距。在本研究中，我们发现了凝溶胶蛋白（GSN）的新作用，GSN是一种肌动蛋白结合蛋白，在RA患者血浆中的水平显著降低。我们阐明GSN是巨噬细胞中NLRP3炎性小体激活的关键调节因子，这为RA患者中GSN分泌减少提供了合理的解释。我们发现GSN在LPS预处理的巨噬细胞中与NLRP3相互作用，从而调节NLRP3炎性小体复合物的形成。降低GSN表达显著增强NLRP3炎性小体激活。GSN阻止NLRP3向线粒体的转位；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缺陷小鼠关节炎症状的加重表明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炎性小体相关的多种疾病模型中都表现出保护功能。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，骨髓细胞特异性GSN基因敲除小鼠表现出加剧的炎症反应。这些发现提示了调节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带来了希望。
