Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center of Oral Disease, Shanghai, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
Department of Oral Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; National Clinical Research Center of Oral Disease, Shanghai, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai, China.
Phytomedicine. 2021 Jan;80:153381. doi: 10.1016/j.phymed.2020.153381. Epub 2020 Oct 13.
Hyperactivation of B cells by activators has been demonstrated to play a central role in the pathogenesis of Sjögren's syndrome (SS). In this study, we found that artesunate (ART) can attenuate BAFF-induced B cell hyperactivation and SS-like symptoms in NOD/Ltj mice.
To determine the efficacy of ART in attenuating SS-like symptoms in vivo and explore the underlying mechanism in vitro.
ART was intragastrically injected into SS-like NOD/Ltj mice. The cytokine hsBAFF was used to activate Raji and Daudi B cells to mimic B cell hyperactivation in vitro.
The efficacy of ART in inhibiting SS progression was studied in NOD/Ltj mice. Salivary flow rate, the number of lymphocytic infiltration foci, the level of autoantibodies and the extent of B cell infiltration were measured in the indicated groups. CCK-8 assays, flow cytometry-based EdU staining and Annexin V/PI staining were also used to detect the effect of ART on the survival and proliferation mechanism in BAFF-induced Raji and Daudi cells. Further studies determined that TRAF6 degradation is a potential mechanism by which ART determines B cell fate.
Treatment with ART inhibited lymphocytic foci formation, B cell infiltration and autoantibody secretion in SS-like NOD/Ltj mice. In vitro assay results indicated that ART effectively inhibited BAFF-induced viability, survival and proliferation of neoplastic B cells. Mechanistically, ART targeted BAFF-activated NFκB by regulating the proteasome-mediated degradation of TRAF6 in Raji and Daudi cells.
ART ameliorated murine SS-like symptoms and regulated TRAF6-NFκB signaling, thus determining survival and proliferation of B cells.
已证实 B 细胞的激活物超激活在干燥综合征（SS）的发病机制中起核心作用。在这项研究中，我们发现青蒿琥酯（ART）可减轻 NOD/Ltj 小鼠中 BAFF 诱导的 B 细胞过度激活和 SS 样症状。
确定 ART 体内减轻 SS 样症状的疗效，并在体外探索其潜在机制。
ART 通过灌胃注入 SS 样 NOD/Ltj 小鼠。使用 hsBAFF 细胞因子激活 Raji 和 Daudi B 细胞，以模拟体外 B 细胞过度激活。
研究了 ART 在抑制 NOD/Ltj 小鼠 SS 进展中的疗效。在各组中测量唾液流量、淋巴细胞浸润灶数量、自身抗体水平和 B 细胞浸润程度。还使用 CCK-8 测定法、基于流式细胞术的 EdU 染色和 Annexin V/PI 染色来检测 ART 对 BAFF 诱导的 Raji 和 Daudi 细胞存活和增殖机制的影响。进一步的研究确定 TRAF6 降解是 ART 决定 B 细胞命运的潜在机制。
ART 治疗抑制了 SS 样 NOD/Ltj 小鼠中的淋巴细胞灶形成、B 细胞浸润和自身抗体分泌。体外实验结果表明，ART 有效抑制了 BAFF 诱导的肿瘤性 B 细胞活力、存活和增殖。在机制上，ART 通过调节 Raji 和 Daudi 细胞中蛋白酶体介导的 TRAF6 降解来靶向 BAFF 激活的 NFκB。
ART 改善了小鼠 SS 样症状，并调节了 TRAF6-NFκB 信号通路，从而决定了 B 细胞的存活和增殖。
