Li Xiaojing, Fei Fei, Yao Genhong, Yang Xixi, Geng Linyu, Wang Dandan, Gao Yingying, Hou Yayi, Sun Lingyun
Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
Immunology. 2023 Jan;168(1):170-183. doi: 10.1111/imm.13570. Epub 2022 Sep 17.
Emerging studies have reported the expansion of myeloid-derived suppressor cells (MDSCs) in some autoimmune disorders, such as systemic lupus erythematosus (SLE), but the detailed molecular mechanisms of the aberrant expansion in SLE are still unclear. In the present study, we confirmed that the increased MDSCs positively correlated with disease activity in SLE patients. The suppressive capacity of MDSCs from patients with high activity was lower than that of MDSCs from patients with low activity. Moreover, the potential precursors for MDSCs, common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs), were markedly increased in the bone marrow (BM) aspirates of SLE patients. As an important regulator of cell fate decisions, aberrant activation of Notch signalling was reported to participate in the pathogenesis of SLE. We found that the expression of Notch1 and its downstream target gene hairy and enhancer of split 1 (Hes-1) increased markedly in GMPs from SLE patients. Moreover, the Notch1 signalling inhibitor DAPT profoundly relieved disease progression and decreased the proportion of MDSCs in pristane-induced lupus mice. The frequency of GMPs was also decreased significantly in lupus mice after DAPT treatment. Furthermore, the inhibition of Notch1 signalling could limit the differentiation of MDSCs in vitro. The therapeutic effect of DAPT was also verified in Toll-like receptor 7 (TLR7) agonist-induced lupus mice. Taken together, our results demonstrated that Notch1 signalling played a crucial role in MDSC differentiation in SLE. These findings will provide a promising therapy for the treatment of SLE.
新兴研究报道了在一些自身免疫性疾病中，如系统性红斑狼疮（SLE），髓系来源的抑制性细胞（MDSCs）会扩增，但SLE中异常扩增的详细分子机制仍不清楚。在本研究中，我们证实SLE患者中MDSCs增加与疾病活动呈正相关。高活动度患者的MDSCs抑制能力低于低活动度患者的MDSCs。此外，SLE患者骨髓穿刺物中MDSCs的潜在前体细胞，即常见髓系祖细胞（CMPs）和粒细胞-单核细胞祖细胞（GMPs）显著增加。作为细胞命运决定的重要调节因子，Notch信号通路的异常激活被报道参与SLE的发病机制。我们发现SLE患者的GMPs中Notch1及其下游靶基因毛状分裂增强子1（Hes-1）的表达显著增加。此外，Notch1信号抑制剂DAPT可显著缓解疾病进展，并降低 pristane诱导的狼疮小鼠中MDSCs的比例。DAPT治疗后，狼疮小鼠中GMPs的频率也显著降低。此外，抑制Notch1信号通路可在体外限制MDSCs的分化。DAPT的治疗效果在Toll样受体7（TLR7）激动剂诱导的狼疮小鼠中也得到了验证。综上所述，我们的结果表明Notch1信号通路在SLE的MDSC分化中起关键作用。这些发现将为SLE的治疗提供一种有前景的疗法。
