Lupus nephritis: glycogen synthase kinase 3β promotion of renal damage through activation of the NLRP3 inflammasome in lupus-prone mice.
Lupus nephritis: glycogen synthase kinase 3β promotion of renal damage through activation of the NLRP3 inflammasome in lupus-prone mice.
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糖原合酶激酶 3 beta 通过激活狼疮易感小鼠的 NLRP3 炎症小体促进肾损伤
DOI：
10.1002/art.38993
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Fu SM
中科院分区：
文献类型：
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作者：
Zhao J;Wang H;Huang Y;Zhang H;Wang S;Gaskin F;Yang N;Fu SM
糖原合成酶激酶3β（Glycogen synthase kinase 3β，GSK-3β）通过多种信号通路参与免疫和炎症反应，导致促炎细胞因子的产生。本研究旨在探讨GSK-3β在2种狼疮性肾炎小鼠模型中的作用。将GSK-3β选择性抑制剂噻二唑烷酮8（TDZD-8）腹腔注射给12周龄MRL/lpr小鼠8周或22周龄（NZB × NZW）F1小鼠12周。分析GSK-3β和NLRP 3炎性体组分的表达。检测蛋白尿、生化指标、促炎细胞因子、抗双链DNA抗体水平和肾脏病理。在体外，在来自小鼠的骨髓源性巨噬细胞（BERK）和J774A.1巨噬细胞系中评价GSK-3β定向的小干扰RNA（siRNA）对NLRP 3炎性小体活化的作用。在两种模型中，严重蛋白尿和肾脏炎症的发生率显著减弱，抗dsDNA抗体产生、肾脏中免疫复合物沉积和循环促炎细胞因子水平显著降低。TDZD-8抑制GSK-3β和caspase 1的活化，同时减少白细胞介素-1 β（IL-1β）的合成。体外实验中，GSK-3β siRNA转染小鼠骨髓瘤细胞和J774A.1细胞后，GSK-3β的表达、caspase 1的活化和IL-1β的产生均受到抑制。这些结果表明GSK-3β至少部分通过激活NLRP 3/IL-1β途径促进狼疮性肾炎。GSK-3β与NLRP 3/IL-1β通路的连接是我们研究中的新观察。我们的研究结果表明GSK-3β/NLRP 3/IL-1β通路可能是人类狼疮的潜在治疗靶点。
Glycogen synthase kinase 3β (GSK-3β) has been demonstrated to be involved in immune and inflammatory responses via multiple signaling pathways, leading to the production of proinflammatory cytokines. The purpose of this study was to investigate the role of GSK-3β in the pathogenesis of lupus nephritis in 2 mouse models. Thiadiazolidinone 8 (TDZD-8), a selective inhibitor of GSK-3β, was administered intraperitoneally to 12-week-old MRL/lpr mice for 8 weeks or to 22-week-old (NZB × NZW)F1 mice for 12 weeks. The expression of GSK-3β and NLRP3 inflammasome components was analyzed. Proteinuria, biochemical parameters, proinflammatory cytokines, anti–double-stranded DNA (anti-dsDNA) antibody levels, and renal pathology were examined. In vitro, the effect of GSK-3β–directed small interfering RNA (siRNA) on NLRP3 inflammasome activation was evaluated in bone marrow–derived macrophages (BMMs) from the mice and in the J774A.1 macrophage cell line. The incidence of severe proteinuria and renal inflammation was significantly attenuated in both models, with a significant reduction in anti-dsDNA antibody production, immune complex deposition in the kidney, and circulating proinflammatory cytokine levels. TDZD-8 inhibited the activation of GSK-3β and caspase 1, with a concomitant decrease in interleukin-1β (IL-1β) synthesis. In vitro, GSK-3β siRNA transfection of mouse BMMs and the J774A.1 cell line with GSK-3β siRNA inhibited the expression of GSK-3β, the activation of caspase 1, and the production of IL-1β. These results show that GSK-3β promotes lupus nephritis at least partly by activating the NLRP3/IL-1β pathway. The linking of GSK-3β to the NLRP3/IL-1β pathway is a novel observation in our study. Our results suggest that the GSK-3β/NLRP3/IL-1β pathway may be a potential therapeutic target for lupus in humans.