系统性红斑狼疮G-MDSCs通过lncRNA NEAT1调控B细胞自噬的机制研究

Systemic Lupus Erythematosus (SLE) is a typical systemic autoimmune disease characterized by the increased production of IFN-α, which leads to hyperactivation of the immune system and breaks the immunologic tolerance. Recent studies showed that B cells from SLE patients showed a higher level of autophagy, which is required for plasmablast development and IFN-α could induce autophagy of B cells through the JAK-STAT1 signaling pathway. As is known, myeloid-derived suppressor cells (MDSCs) play a key role in modulating the balance and conversion of the immunologic tolerance. We previously found that patients with SLE show a higher level of accumulation of MDSCs in blood compared with healthy control subjects and the percentage of MDSCs in PBMCs was positively correlated with the SLEDAI, which hint that MDSCs may participate in the pathogenesis of SLE. However, it’s still unknown whether MDSCs from SLE can regulate the autophagy of B cells induced by IFN-α. Interestingly, we found that G-MDSCs, one subpopulation of MDSCs, were significantly accumulated in the spleen and bone marrow of MRL/lpr mice; in vitro study showed that G-MDSCs could promote IFN-α-induced activation of JAK-STAT1 signaling pathway in B cells through IL-1β; we screened a lncRNA—NEAT1 which is highly expressed in G-MDSCs from MRL/lpr mice and overexpression of NEAT1 could promote the secretion of IL-1β. We conclude that NEAT1 may regulate the autophagy of B cells induced by IFN-α by promoting the secretion of IL-1β in G-MDSCs. Thus, this study will clarify the mechanism that how G-MDSCs regulate the autophagy of B cells induced by IFN-α through NEAT1 and provide a new theory for understanding the mechanism of the pathogenesis of SLE.

SLE患者B细胞自噬水平增强，自噬可促进浆母细胞发育参与SLE发病。我们报道MDSCs随着SLE发病进程在外周血中募集，提示其可能参与SLE发病。但迄今仍不清楚狼疮MDSCs对B细胞自噬的影响。已知干扰素-α诱导B细胞自噬。我们发现G-MDSCs在狼疮小鼠体内募集；狼疮G-MDSCs通过分泌IL-1β促进B细胞中干扰素-α下游通路活化；我们筛选出一个在狼疮G-MDSCs中高表达且促进IL-1β表达的lncRNA—NEAT1。我们推测，NEAT1可能通过促进狼疮G-MDSCs分泌IL-1β调控B细胞中干扰素-α诱导的自噬，进而参与SLE发病。本项目将分析狼疮G-MDSCs分泌的IL-1β对B细胞自噬的影响；揭示NEAT1促进狼疮G-MDSCs分泌IL-1β的机制；体内评估狼疮G-MDSCs中NEAT1对B细胞自噬及SLE发病的调控作用。本项目将为揭示SLE的发病机制及治疗提供新思路和新策略。

已知系统性红斑狼疮（SLE）患者B细胞自噬水平增强，我们前期研究发现干扰素-α（IFN-α）显著诱导B细胞自噬，并且SLE患者外周血B细胞中IFN-I通路过度活化，但具体机制仍不清楚。因此，急需探索SLE患者B细胞IFN-I通路过度活化的机制。我们前期报道骨髓来源的抑制性细胞（MDSCs）随着SLE发病进程在外周血中募集，提示其可能参与SLE发病。但迄今仍不清楚狼疮MDSCs对B细胞IFN-I通路活化及自噬的影响。本项目结合动物模型、细胞水平研究及临床样本展开研究，明确了MDSCs在狼疮发病过程中的作用；研究了狼疮G-MDSCs通过高表达长链非编码RNA NEAT1调控B细胞IFN-I通路活化及自噬的影响及其具体机制；探究SLE患者外周血MDSCs中NEAT1表达与PBMCs中IFN-I诱导基因之间的相关性。. 主要研究结果如下：我们发现随着MRL/lpr自发狼疮小鼠周龄变大，MDSCs，包括其两个亚型粒细胞样MDSCs（G-MDSCs）和单核样MDSCs（M-MDSCs），在其脾脏显著扩增；体外实验表明狼疮G-MDSCs，而非M-MDSCs，能够促进B细胞中IFN-I通路活化；删除MDSCs可显著改善MRL/lpr小鼠病情并且抑制B细胞中IFN-I通路活化，而过继转移狼疮G-MDSCs则显著加重MRL/lpr小鼠病情并且促进B细胞中IFN-I通路活化；我们筛选出一个在狼疮G-MDSCs中显著高表达的lncRNA—NEAT1，NEAT1能够增强G-MDSCs对B细胞IFN-I通路活化的促进作用；与MRL/lpr小鼠相比，缺失NEAT1的MRL/lpr小鼠狼疮样病情减轻并且脾脏B细胞IFN-I通路活化程度降低；SLE患者外周血单个核细胞（PBMCs）中NEAT1的表达水平与IFN-I诱导基因的表达显著正相关。本研究阐明了狼疮G-MDSCs通过促进B细胞中IFN-I通路活化参与SLE发病的机制，从新的角度揭示SLE发病的机理，为人们研究SLE的发病机制及治疗提供新思路和新策略。