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Tris DBA Ameliorates Accelerated and Severe Lupus Nephritis in Mice by Activating Regulatory T Cells and Autophagy and Inhibiting the NLRP3 Inflammasome
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-02-14 , DOI: 10.4049/jimmunol.1801610
Chung-Yao Wu , Kuo-Feng Hua , Ching-Liang Chu , Shin-Ruen Yang , Jack L. Arbiser , Sung-Sen Yang , Yu-Chuan Lin , Feng-Cheng Liu , Shun-Min Yang , Shuk-Man Ka , Ann Chen

Key Points Tris DBA ameliorates lupus nephritis in a murine lupus model. Tris DBA regulates the NLRP3 inflammasome by blunting MAPK and enhancing autophagy. Tris DBA enhances Treg cell function and inhibits DC-mediated T cell activation. Tris (dibenzylideneacetone) dipalladium (Tris DBA), a small-molecule palladium complex, has been shown to inhibit cell growth and proliferation in pancreatic cancer, lymphocytic leukemia, and multiple myeloma. In the current study, we examined the therapeutic effects of Tris DBA on glomerular cell proliferation, renal inflammation, and immune cells. Treatment of accelerated and severe lupus nephritis (ASLN) mice with Tris DBA resulted in improved renal function, albuminuria, and pathology, including measurements of glomerular cell proliferation, cellular crescents, neutrophils, fibrinoid necrosis, and tubulointerstitial inflammation in the kidneys as well as scoring for glomerulonephritis activity. The treated ASLN mice also showed significantly decreased glomerular IgG, IgM, and C3 deposits. Furthermore, the compound was able to 1) inhibit bone marrow–derived dendritic cell–mediated T cell functions and reduce serum anti-dsDNA autoantibody levels; 2) differentially regulate autophagy and both the priming and activation signals of the NLRP3 inflammasome; and 3) suppress the phosphorylation of JNK, ERK, and p38 MAPK signaling pathways. Tris DBA improved ASLN in mice through immunoregulation by blunting the MAPK (ERK, JNK)-mediated priming signal of the NLRP3 inflammasome and by regulating the autophagy/NLRP3 inflammasome axis. These results suggest that the pure compound may be a drug candidate for treating the accelerated and deteriorated type of lupus nephritis.

中文翻译:

Tris DBA 通过激活调节性 T 细胞和自噬以及抑制 NLRP3 炎症小体来改善小鼠的加速和严重狼疮性肾炎

关键点 Tris DBA 可改善小鼠狼疮模型中的狼疮性肾炎。Tris DBA 通过钝化 MAPK 和增强自噬来调节 NLRP3 炎症小体。Tris DBA 可增强 Treg 细胞功能并抑制 DC 介导的 T 细胞活化。Tris(二亚苄基丙酮)二钯(Tris DBA)是一种小分子钯复合物,已被证明可抑制胰腺癌、淋巴细胞白血病和多发性骨髓瘤的细胞生长和增殖。在当前的研究中,我们检查了 Tris DBA 对肾小球细胞增殖、肾脏炎症和免疫细胞的治疗作用。用 Tris DBA 治疗加速和严重狼疮性肾炎 (ASLN) 小鼠可改善肾功能、蛋白尿和病理,包括测量肾小球细胞增殖、细胞新月体、中性粒细胞、纤维蛋白样坏死、和肾小管间质炎症以及肾小球肾炎活动评分。治疗后的 ASLN 小鼠还显示出肾小球 IgG、IgM 和 C3 沉积物显着减少。此外,该化合物能够 1) 抑制骨髓来源的树突状细胞介导的 T 细胞功能并降低血清抗 dsDNA 自身抗体水平;2) 差异调节自噬以及 NLRP3 炎症小体的启动和激活信号;3) 抑制 JNK、ERK 和 p38 MAPK 信号通路的磷酸化。Tris DBA 通过减弱 MAPK (ERK, JNK) 介导的 NLRP3 炎症小体的启动信号和调节自噬/NLRP3 炎症小体轴,通过免疫调节改善小鼠的 ASLN。
更新日期:2020-02-14
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