MCPIP1负反馈抑制NLRP3炎症小体激活在糖尿病视网膜病变中的作用

The main pathological features of diabetic retinopathy (DR) in the early stage are pericyte loss, acellular capillary formation, microaneurysm and capillary basement membrane thickening, which is associated with systemic and local long-standing chronic low-grade inflammation and leukocyte stasis . Our recent studies have found that the activation of NOD like receptor protein 3 (NLRP3) inflammasome leads to a chronic low-grade inflammation in DR. In recent years, monocyte chemotactic protein-1 induced protein-1 (MCPIP1) has been found to have a negative feedback effect on the inhibition of inflammation. We found that MCPIP1 was highly expressed in the retina of diabetic rats, and was positively correlated with the activation of NLRP3 inflammasome, but its effect is not clear. Therefore, by using recombinant DNA technology， this study is designed to, firstly, discuss the effects of high glucose induced NLRP3 inflammasome activation on the expression of MCPIP1; secondly, clarify whether MCPIP1 negative feedback regulate NLRP3 inflammasome activation through inhibition of NF kappa B pathway, which reduces inflammation and leukocyte stasis. This will reveal that MCPIP1 may be an effective therapeutic target for DR, deepen people's understanding of the pathogenesis of DR, and provide theoretical and experimental basis for the prevention and treatment of DR, which has important theoretical and practical significance.

糖尿病性视网膜病变（DR）早期的主要病理特征是毛细血管周细胞丢失、无细胞毛细血管形成、微血管瘤和毛细血管基底膜增厚，与全身及局部长期存在的慢性低度炎症以及白细胞瘀滞有关。我们近期的研究发现，NOD样受体蛋白3（NLRP3）炎症小体的激活导致了DR的慢性低度炎症。近年来，单核细胞趋化蛋白质1诱导蛋白（MCPIP1）被发现具有负反馈抑制炎症的作用。我们发现MCPIP1在糖尿病大鼠视网膜组织高表达，且与NLRP3炎症小体激活呈正相关，但作用不明。因此，本课题运用基因重组技术，首先探讨高糖状态下NLRP3炎症小体的活化对MCPIP1表达的诱导作用，其次阐明MCPIP1是否通过抑制NF-κB通路激活负反馈调控NLRP3炎症小体激活，从而减轻炎症反应，减少白细胞瘀滞。这将揭示MCPIP1可能成为DR的有效治疗靶点，加深人们对DR发病机制的认识，为DR防治提供理论和实验依据，具有重要的理论和现实意义。

糖尿病性视网膜病变（DR）的发病机制与全身及局部长期存在的慢性低度炎症以及白细胞瘀滞有关。国内外大量研究发现，NOD样受体蛋白3（NLRP3）炎症小体的激活导致了DR的慢性低度炎症。而单核细胞趋化蛋白质1诱导蛋白（MCPIP1）近年来被发现具有负反馈抑制炎症的作用。本课题组前期研究发现MCPIP1在糖尿病大鼠视网膜组织高表达，且与NLRP3炎症小体激活呈正相关，但作用不明。因此，本项目通过细胞实验和动物实验明确了MCPIP1与NLRP3炎症小体相互作用在DR发生发展中的作用机制。细胞实验结果提示高糖刺激使得人视网膜血管内皮细胞中（HREC）中NLRP3炎症小体被激活，分泌成熟的IL-1β增多，IL-1β诱导MCPIP1蛋白表达增加。使用荧光素标记的人单核细胞系THP-1细胞发现其对HREC的粘附率增加。而过表达MCPIP1则可抑制NLRP3炎症小体激活，同时降低THP-1细胞对HREC细胞的粘附率，沉默MCPIP1则起到相反的作用。进一步的研究表明MCP1P1是通过抑制NF-κB通路负反馈调控NLRP3炎症小体的激活。动物实验中获得的结果与细胞实验类似。以上结果证实了MCPIP1在DR病理生理过程中的重要作用，为DR的基因治疗奠定了理论和实践基础。