中性粒细胞胞外诱捕网（NETs）调节蜕膜NK细胞对系统性红斑狼疮患者妊娠胎盘损伤的机制研究

Pregnancy complicated with systemic lupus erythematosus (SLE) is a high-risk pregnancy. There is a significant abnormality in the pathology of placenta in SLE patients, but the cell molecular mechanism of this damage has not been reported. The decidual natural killer cells (dNK) participate in the process of embryonic development and protection in normal pregnancy. However, it will be activated abnormally by inflammation, and cause apoptosis of trophoblasts, following by a series of obstetric complications. Neutrophil extracellular traps (NETs) play an important role in the pathogenesis of SLE. Our previous studies found that patients with SLE had more NETs infiltration in their placenta than normal pregnancies; and the degree of infiltration was associated with adverse pregnancy outcomes. Moreover, the infiltration of dNK is positively correlated with NETs and there is a change in subtype distribution. Therefore, we hypothesize that, in SLE, the placenta is damaged by NETs as a target organ, which increase corresponding pro-inflammatory cytokines. These cytokines cause abnormal activation of dNK, resulting in placental damage, and ultimately leads to SLE adverse pregnancy outcome. This project studies the mechanism of NETs regulating dNK on placental impairment in SLE pregnancy, aiming to improve SLE pregnancy outcomes and explore new targets for clinical diagnosis and treatment.

妊娠合并系统性红斑狼疮（SLE）属于高危妊娠，其胎盘存在明显病理异常，但其分子机制尚未有深入研究。胎盘中的蜕膜自然杀伤细胞（dNK）在正常妊娠情况下，参与多种胚胎发育和保护作用。但当其受到炎症等刺激后，其细胞异常激活，可导致滋养细胞凋亡并引发一系列产科并发症。其中，中性粒细胞胞外诱捕网（NETs）在SLE致病机制和器官损伤中具有重要作用。前期研究发现SLE患者与正常妊娠者相比，其胎盘有较多的NETs浸润且其浸润程度与不良妊娠结局相关；并且SLE胎盘中dNK的浸润程度与NETs呈正相关性，且存在亚型分布的变化。因此，本项目提出胎盘作为靶器官，在SLE疾病中因NETs诱发损伤，即NETs引起相应促炎因子增加并异常激活dNK，进而造成胎盘结构和功能破坏，最终导致SLE不良妊娠结局。本项研究旨在改善SLE妊娠结局并为其临床诊治探索新的靶点。

本项目主要研究中性粒细胞胞外诱捕网（NETs）通过调控dNK细胞介导SLE患者胎盘损伤，引发不良妊娠结局。在该项目执行过程中，本课题组成功建立了妊娠合并SLE的小鼠模型，并构建和完善了SLE妊娠的临床资料样本库。该项目按计划进展顺利，在研究中发现大量中性粒细胞浸润在SLE妊娠胎盘组织中，且NETs的浸润和妊娠结局显著相关。NETs和CD56+CD16+dNK细胞的浸润，在SLE妊娠合并胎盘功能不全的个体中显著增加且存在相关性。研究表明NETs可能通过dNK导致胎盘免疫紊乱和SLE妊娠的病理变化，为进一步探索SLE在胎盘损伤中的作用机制提供研究基础。同时课题结合临床研究建立了妊娠合并SLE发生子痫前期的预测模型和风险评估系统，同时探索了妊娠合并SLE的胎儿不良妊娠结局高危因素。本项目从临床和基础两方面来探索妊娠合并SLE的不良妊娠结局，有助于更好的理解SLE对妊娠结局的影响作用及机制，为提高SLE妊娠结局及发展新的治疗靶点打下基础。