MAP1LC3B参与狼疮性肾炎足细胞损伤的机制研究

Lupus nephritis (LN) is the most common and severe complication of systemic lupus erythematosus (SLE), which significantly increased morbidity and mortality in SLE. The incidence of LN in China is high, and its exact pathogenesis still remains unclear. Our previous studies found that: autophagy could protect podocytes from injury in lupus nephritis; the genetic variation of LC3B coding gene MAP1LC3B increased the susceptibility to SLE, possibly through up-regulation of the expression of MAP1LC3B; MAP1LC3B overexpression podocyte cell line increased the combination of MAP1LC3B and FAS. Thus, we hypothesized that in lupus nephritis, on the one hand MAP1LC3B could protect podocytes from injury by forming autophagosomes (which has been confirmed by our previous studies); on the other hand, it might also induce podocyte injury by interacting with apoptotic proteins (we will demonstrate in this study). In the present project, we will focus on the role of MAP1LC3B in the pathogenesis of lupus nephritis podocyte injury in order to provide theoretical basis for finding therapeutic targets for lupus nephritis.

狼疮性肾炎（LN）是系统性红斑狼疮（SLE）最常见的严重并发症。我国LN发病率高，患者常合并足细胞损伤，其确切的发病机制仍不清楚。我们前期研究结果发现：LN中，自噬能够起到缓解损伤保护足细胞的作用；然而自噬相关蛋白LC3B编码基因MAP1LC3B遗传变异增加SLE易感性，且可能通过上调MAP1LC3B表达参与SLE发病；过表达MAP1LC3B的足细胞系，MAP1LC3B与FAS结合增加，提示可能促进细胞凋亡。据此提出研究假说：LN中，MAP1LC3B转录翻译产生LC3B，一方面通过构成自噬体，起到保护足细胞的作用（我们既往研究已经证实）；另一方面可能通过与凋亡相关蛋白相互作用，引起足细胞损伤，促进狼疮性肾炎进展（本研究将要论证的内容）。本课题拟通过临床样本检测和机制研究相结合，探究MAP1LC3B参与LN足细胞损伤的分子机制，为寻找狼疮性肾炎治疗靶标提供理论依据。

狼疮性肾炎（LN）是系统性红斑狼疮（SLE）最常见的严重并发症，常合并足细胞损伤。然而其发病机制仍不十分清楚。我们提取了LN患者和健康人循环IgG作为重要的LN致足细胞损伤因素，构建了MAP1LC3B敲除的足细胞系，以及应用自噬激动剂和抑制剂，结果显示：敲除MAP1LC3B，NLRP3炎性小体活性增加；通过回复实验过表达MAP1LC3B能够减少NLRP3炎性小体的活化，提示在狼疮性肾炎NLRP3炎性小体产生中MAP1LC3B发挥保护作用。由于MAP1LC3B是重要的自噬标记物，接下来我们探讨了自噬在狼疮性肾炎足细胞损伤中的作用，结果发现：应用自噬抑制剂后，足细胞NLRP3炎性小体上调，足细胞损伤增加；应用自噬激活剂能够减少NLRP3炎性小体活化，缓解足细胞损伤。我们进一步探讨了MAP1LC3B上游的调控分子，通过应用基因敲除的细胞系发现CD36能够调控MAP1LC3B的表达，进而调控NLRP3炎性小体的活化以及足细胞损伤。综上所述，狼疮性肾炎足细胞中CD36表达上调，能够抑制MAP1LC3B表达，引起NLRP3炎性小体活化，促进足细胞损伤。过表达MAP1LC3B或者应用自噬激活剂能够减少NLRP3炎性小体产生，缓解足细胞损伤。本课题通过探讨重要的自噬相关蛋白MAP1LC3B在狼疮性肾炎足细胞损伤中的作用，发现MAP1LC3B及其上游调控分子CD36有望成为狼疮性肾炎潜在的药物治疗靶点。