Li Baihui, Yue Yan, Dong Chunsheng, Shi Yongbing, Xiong Sidong
Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, China.
Clin Exp Rheumatol. 2014 Sep-Oct;32(5):705-14. Epub 2014 Aug 15.
Systemic lupus erythematosus (SLE) is a typical inflammatory autoimmune disease for its unknown pathogenesis and potential fatality. It has been reported that autophagy has a crosstalk with autoimmunity, but its impact on the pathogenesis of SLE remains unclear. Here, we investigated the role of autophagy in inflammatory response of macrophages under SLE conditions.
First, we detected the expression of autophagy-related genes (Atg5, Atg12 and Beclin 1) in the macrophages derived from activated lymphocytes-derived DNA (ALD-DNA) induced murine lupus as well as in the PBMC from SLE patients. And then through adoptive transfer of Beclin 1 knockdown macrophages, we further investigated the potential effect of macrophage autophagy on the SLE-associated inflammatory response and disease severity by evaluating serum anti-dsDNA antibodies and proteinuria levels, immune complex deposition as well as renal pathological changes.
We found that autophagy related genes were significantly upregulated in the splenic and renal macrophages of lupus mice and in the PBMC of SLE patients. Adoptive transfer of Beclin 1 knockdown macrophages could significantly decrease the anti-dsDNA antibodies and proteinuria levels, robustly reduce renal immune complex deposition and remit glomerulonephritis, indicating the amelioration of murine lupus. This protective effect was associated with the obviously decreased production of proinflammatory cytokines IL-6 and TNF-α.
Our results suggested that aberrant activated autophagy in macrophages contributed to the pathogenesis of murine lupus possibly via promoting the production of proinflammatory cytokines TNF-α and IL-6, and inhibition of autophagy might represent a novel regulation strategy for excessive activation of proinflammatory macrophages and a new therapeutic regime for SLE.
系统性红斑狼疮（SLE）是一种典型的炎症性自身免疫性疾病，其发病机制不明且具有潜在致死性。据报道，自噬与自身免疫存在相互作用，但其对SLE发病机制的影响仍不清楚。在此，我们研究了自噬在SLE条件下巨噬细胞炎症反应中的作用。
首先，我们检测了来源于活化淋巴细胞衍生DNA（ALD-DNA）诱导的小鼠狼疮巨噬细胞以及SLE患者外周血单个核细胞（PBMC）中自噬相关基因（Atg5、Atg12和Beclin 1）的表达。然后，通过过继转移Beclin 1基因敲低的巨噬细胞，我们通过评估血清抗双链DNA抗体和蛋白尿水平、免疫复合物沉积以及肾脏病理变化，进一步研究巨噬细胞自噬对SLE相关炎症反应和疾病严重程度的潜在影响。
我们发现狼疮小鼠脾脏和肾脏巨噬细胞以及SLE患者PBMC中自噬相关基因显著上调。过继转移Beclin 1基因敲低的巨噬细胞可显著降低抗双链DNA抗体和蛋白尿水平，强力减少肾脏免疫复合物沉积并缓解肾小球肾炎，表明小鼠狼疮病情改善。这种保护作用与促炎细胞因子IL-6和TNF-α的产生明显减少有关。
我们的结果表明，巨噬细胞中异常激活的自噬可能通过促进促炎细胞因子TNF-α和IL-6的产生而促成小鼠狼疮的发病机制，抑制自噬可能代表一种针对促炎巨噬细胞过度激活的新型调控策略以及SLE的一种新治疗方案。
