The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China.
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, PR China; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China; Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, PR China.
Free Radic Biol Med. 2019 Nov 1;143:260-274. doi: 10.1016/j.freeradbiomed.2019.08.013. Epub 2019 Aug 13.
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-β-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-β-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.
系统性红斑狼疮（SLE）是一种慢性自身免疫性炎症性疾病，其特征为多器官损伤。然而，髓系来源的抑制细胞（MDSCs）衰老是否存在并参与 SLE 的发病机制尚不清楚。二氢青蒿素（DHA）是否通过减轻 MDSCs 衰老来缓解 SLE 的症状仍不得而知。在本研究中，我们使用 SA-β-半乳糖苷染色、衰老相关分泌表型（SASP）和衰老相关蛋白 P21、P53 和 P16 的 Western blot 分析来测量 SLE 中 MDSCs 的衰老。我们确定 MDSCs 衰老通过适应性转移 MDSCs 实验促进 SLE 进展。同时，我们通过组织病理学检测、Western blot 分析、免疫荧光、QPCR 和流式细胞术分析进一步表明 DHA 通过改善 pristane 诱导的狼疮症状。DHA 通过检测 SA-β-半乳糖苷染色、衰老相关分泌表型（SASP）和衰老相关蛋白 P21、P53 和 P16 的 Western blot 分析来逆转 MDSCs 衰老。此外，机制分析表明，Nrf2 的特异性拮抗剂 ML385 阻断了 DHA 对 MDSCs 衰老的抑制作用，这表明 DHA 对 MDSCs 衰老的作用依赖于 Nrf2/HO-1 通路的诱导。值得注意的是，我们通过适应性转移 DHA 处理的 MDSCs 实验揭示了 DHA 通过抑制 MDSCs 衰老来改善 SLE 发展的机制。总之，MDSCs 衰老在 SLE 的发病机制中起着重要作用，DHA 通过减轻 MDSCs 衰老来缓解 SLE 的症状，这种衰老涉及 Nrf2/HO-1 通路的诱导。
