MSC通过抑制lipocalin 2调控巨噬细胞表型与功能治疗SLE的机制研究

Systemic lupus erythematosus (SLE) is a classical inflammatory autoimmune disease. Lupus nephritis (LN) is a common complication of SLE. Abnormal phenotype and deficient phagocytic function of macrophages are involved in the pathogenesis of SLE. LCN2 is a biomarker of LN. LCN2 has been suggested to contribute to the development of inflammation via regulating macrophage phenotype and may be a new target for the treatment of SLE. Mesenchymal stem cell (MSC) has been confirmed to exert therapeutic effects on SLE. In previous study, we observed high levels of LCN2 in serum of patients with SLE. LCN2 enhanced inflammatory cytokine production and inhibited phagocytic function of apoptotic cells by macrophage. While MSC could drive the generation of macrophage with anti-inflammatory profile and enhance macrophage phagocytosis. Studies have shown that MSC could inhibit the expression of LCN2. Therefore, we hypothesized that regulating macrophage phenotype and function by inhibiting LCN2 expression might be one of the mechanisms for the effective treatment of SLE with MSC. In the present study, we will further investigate the regulatory mechanism of LCN2 on macrophage, inhibitory mechanism of MSC on LCN2, thereby to find out the role of LCN2 in the pathogenesis of SLE and treatment of SLE with MSC. The study may provide a novel theoretical basis for the clinical application of MSC in SLE treatment.

系统性红斑狼疮（SLE）是经典自身免疫病，狼疮肾炎（LN）是SLE常见并发症，巨噬细胞表型失衡、吞噬功能减弱在SLE发病中起重要作用。Lipocalin 2（LCN2）是LN的生物标志物，研究发现LCN2可通过调控巨噬细胞表型参与炎症反应，可能成为SLE治疗新靶点。间充质干细胞（MSC）移植治疗SLE取得显著疗效，但机制尚不明确。我们前期研究发现LCN2在SLE患者血清中显著升高，且LCN2促进巨噬细胞向促炎型转化并抑制其吞噬功能，而MSC可促进巨噬细胞向抑炎型转化并增强其吞噬功能。目前已有文献报道MSC可抑制LCN2表达。因此，我们推测抑制LCN2表达进而调控巨噬细胞表型及功能可能是MSC治疗SLE的机制之一。本项目将进一步研究LCN2调控SLE巨噬细胞机制，阐明MSC下调LCN2的机制，解析LCN2在SLE发病及MSC治疗SLE中的意义，为MSC有效治疗SLE提供新的理论依据。

系统性红斑狼疮（SLE）是一种慢性全身性自身免疫病，狼疮性肾炎（LN）是严重的SLE并发症，是导致患者死亡的主要原因。中性粒细胞明胶酶相关脂质运载蛋白（LCN2）是LN的生物标志物，对LN早期诊断、病情监测及预后评估有重要意义。本项目通过分析LCN2表达与LN临床指标的相关性，利用狼疮鼠模型研究LCN2在LN中的致病作用，从而阐明LCN2参与LN发生发展的具体机制；采用间充质干细胞（MSC）治疗狼疮鼠模型并探索了其治疗机制。结果发现，LN肾脏中除了肾脏定居细胞外，浸润的白细胞也可以分泌LCN2，引起LCN2升高，而外周血单个核细胞可以是LCN2升高的肾外来源，高表达的LCN2与LN患者临床病情及肾脏病理损害均显著相关；LCN2通过IL-12/STAT4途径以自分泌或旁分泌方式促进Th1细胞分化加重LN，抑制LCN2可减轻诱导性和自发性狼疮模型的肾脏炎症；MSC移植可以有效治疗MRL/lpr狼疮小鼠，改善狼疮小鼠肾脏病理；机制研究发现MSC通过抑制LCN2促进巨噬细胞表达抑炎因子IL-10进而治疗SLE。这些发现不仅丰富LN发病机制的新理论，而且拓展了SLE治疗的新思路和新靶点。另外，阐明了MSC治疗SLE的效果和作用机制，为临床推广应用MSC治疗SLE提供了有力的理论依据。