Protective effect of dihydroartemisinin in inhibiting senescence of myeloid-derived suppressor cells from lupus mice via Nrf2/HO-1 pathway
Protective effect of dihydroartemisinin in inhibiting senescence of myeloid-derived suppressor cells from lupus mice via Nrf2/HO-1 pathway
复制标题
双氢青蒿素通过 Nrf2/HO-1 通路抑制狼疮小鼠髓源性抑制细胞衰老的保护作用
DOI：
10.1016/j.freeradbiomed.2019.08.013
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发表时间：
2019-11-01
影响因子：
7.4
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
--
作者：
Li, Dan;Qi, Jingjing;Hou, Yayi
系统性红斑狼疮(SLE)是一种以多器官损害为特征的慢性自身免疫性炎症性疾病。然而，髓系抑制细胞(MDSCs)是否存在衰老并参与SLE的发病机制尚不清楚。双氢青蒿素(DHA)是否通过缓解MDSCs的衰老来减轻SLE的症状仍不清楚。在本研究中，我们用SA-β-Gal染色、衰老相关分泌表型(SASP)和衰老相关蛋白P21、P53和P16的蛋白质印迹分析来检测SLE中MDSCs的衰老。通过适应性转移MDSCs的检测，我们发现MDSCs的衰老促进了SLE的进展。同时，通过组织病理学检测、Western印迹分析、免疫荧光、定量聚合酶链式反应和流式细胞仪分析，进一步证明DHA可以改善狼疮大鼠的症状。DHA通过检测SA-β-Gal染色、衰老相关分泌表型(SASP)和衰老相关蛋白P21、P53和P16的蛋白印迹分析来逆转MDSCs的衰老。进一步的机制分析表明，DHA对MDSCs衰老的抑制作用可被Nrf2的特异性拮抗剂ML385阻断，这表明DHA对MDSCs衰老的抑制作用依赖于Nrf2/HO-1通路的诱导。值得注意的是，通过自适应转移DHA处理的MDSCs的检测，我们发现DHA抑制MDSCs的衰老以改善SLE的发展。结论：MDSCs衰老在SLE发病机制中起重要作用，DHA通过诱导Nrf2/HO-1途径减轻MDSCs衰老，从而减轻SLE症状。
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease characterized by multi-organ injury. However, whether myeloid-derived suppressor cells (MDSCs) senescence exists and participates in SLE pathogenesis remains unclear. And whether dihydroartemisinin (DHA) attenuates the symptoms of SLE via relieving MDSCs senescence remains elusive. In the present study, we measured the senescence of MDSCs in SLE using SA-beta-gal staining, senescence-associated secretory phenotype (SASP) and Western blot analysis of aging-related protein P21, P53 and P16. We identified that the MDSCs senescence promoted the SLE progress by adaptive transfer MDSCs assays. Meanwhile, we further showed DHA ameliorated the symptoms of pristane-induced lupus by histopathological detection, Western blot analysis, immunofluorescence, QPCR and flow cytometry analysis. DHA reversed MDSCs senescence by detecting SA-beta-gal staining, senescence-associated secretory phenotype (SASP) and Western blot analysis of aging-related protein P21, P53 and P16. Furthermore, mechanistic analysis indicated that the inhibitory effect of DHA on MDSCs senescence was blocked by ML385, the specific antagonist of Nrf2, which revealed that the effect of DHA on MDSCs senescence was dependent on the induction of Nrf2/HO-1 pathway. Of note, we revealed that DHA inhibited MDSCs senescence to ameliorate the SLE development by adaptive transfer DHA-treated MDSCs assays. In conclusion, MDSCs senescence played a vital role in the pathogenesis of SLE, and DHA attenuated the symptoms of SLE via relieving MDSCs aging involved in the induction of Nrf2/HO-1 pathway.