IL-33/ST2调控肥大细胞自噬在肾纤维化中的作用及机制

Renal fibrosis is the common ending of chronic kidney disease. It is of great significance for its prevention and early intervention to make the mechanism of its occurrence and development clear. Studies have shown that mast cells play an important role in renal fibrosis, but the mechanism is not clear. We confirmed that the expression of IL-33, ST2 and mast cells were significantly increased at the early stage of renal fibrosis in mice, and mast cells stabilizers reduced renal fibrosis. Furthermore, mast cells were activated by IL-33, accompanied by increased LC3-II/I ratio and autophagosome number. Mast cells activation also promoted VEGF-C expression in renal tubular endothelial cells, which in turn promoted lymphangiogenesis and was closely related to renal fibrosis. Wu thus supposed IL-33/ST2 might promote renal fibrosis through regulating the autophagy of mast cells and followed lymphangiogenesis. To this end, first the expression and clinical significance of IL-33/ST2 and mast cells in kidney and its relationship with renal fibrosis will be explored, then the impact of IL-33 on mast cells autophagy and function will be observed, and whether IL-33 induces renal fibrosis through regulating mast cells autophagy will also be discussed. Finally the mechanism will be explored, providing new ideas to the prevention and treatment of renal fibrosis.

肾脏纤维化是慢性肾脏病进展的最后归宿，明确其发生发展机制对早期预防和干预具有重要的意义。研究表明，肥大细胞在肾纤维化进程中起到重要作用，但机制尚不明确。前期我们证实，IL-33、ST2及肥大细胞在小鼠肾纤维化模型的早期表达显著升高，而加入肥大细胞稳定剂可减轻肾纤维化；进一步发现肥大细胞可被IL-33激活，同时其表达LC3-II/I增加，自噬小体增多并可促使肾小管内皮细胞VEGF-C表达上调，而后者又可促进淋巴管新生并与肾纤维化的程度密切相关。据此推测IL-33/ST2可能通过调控肥大细胞自噬促进淋巴管新生继而诱导肾纤维化。为此，本项目拟首先明确IL-33/ST2、肥大细胞在肾脏组织中的表达及其与肾纤维化的关系和临床意义；接下来观察IL-33对肥大细胞自噬与功能的影响，及其是否通过调控肥大细胞自噬促进淋巴管新生继而诱导肾纤维化；最后对其机制进行初步探讨。为肾纤维化的防治提供新的思路与手段。

近年来，我国慢性肾脏病(CKD)的发病率逐年升高，严重威胁人们的健康和生命安全，给社会带来了沉重的经济负担，因此防治是目前临床关注的重点。肥大细胞是先天性免疫系统的一种重要的效应细胞，虽然肥大细胞几乎不存在于正常肾组织中，但是临床研究发现，CKD患者血清中肥大细胞类胰蛋白酶水平显著升高，肾间质肥大细胞大量浸润与CKD患者的预后密切相关。IL33属于IL-1细胞因子家族，在先天免疫反应中发挥重要作用，研究发现，IL33/ST2能调节肥大细胞凋亡，提高肥大细胞存活率。在本研究中我们首先收集300例CKD患者的肾穿组织标本和临床资料，发现随着肾小管损伤程度及间质纤维化程度的加重，肾脏组织内肥大细胞浸润数量明显增多，且肥大细胞浸润数目与纤维化程度和血肌酐均呈正相关。在UUO模型中，通过肥大细胞膜稳定剂和肥大细胞敲除小鼠，我们明确肾脏内肥大细胞的浸润可促进肾脏纤维化。其机制可能与损伤的肾小管上皮细胞大量分泌IL-33，IL-33通过其受体ST2作用于肥大细胞，一方面通过减弱其自噬而促进肥大细胞内钙离子的聚集，促进组胺和β-己糖胺酶的释放，使得细胞脱颗粒发挥促进纤维化的作用；另一方面通过减弱其自噬而促进中性粒细胞的趋化，炎性因子的释放，达到促进肾脏纤维化的作用，这也是我们首次报道肾脏内IL33能通过抑制肥大细胞自噬促进肾脏纤维化的进展。