肾脏巨噬细胞中TRIM27调控肾缺血再灌注损伤的作用和机制研究

Kidney macrophages activation and proinflammatary factors expresion play crucial role in kidney ischemia reperfusion injury (IRI), the molecular mechanism of modulation of kidney macrophage activation and proinflammatary factors expresion is the key scientific question for kidney IRI. The applicant has been involved in the clinical diagnostic and treatment and scientific research of kidney IRI for years. In mice kidney ischemia reperfusion injury model, gene expression profiles were used to screen TRIM family gene expression which was proved to be important in the regulation of innate immuninty and inflammatory response, and results showed the expression of TRIM27 significantly elevated.Accordingly, we constructed TRIM27 conditional gene knockout mouse model, then cross-bred with LyzM-Cre mice and succeeded in creating macrophage TRIM27 specific knockout mice. We observed that the development of kidney IRI was obviously promoted and the expression of proflammatory factors was significantly increased in macrophage TRIM27 specific knockout mice when compared with wild-type mice. Based on these results, we tend to clarify the role and molecular mechenism of macrophage TRIM27 in regulating IRI and inflammatory response in kidney, and expect to discover new mechanism and therapy target of kidney IRI.

肾脏巨噬细胞活化和炎症因子表达在移植肾缺血再灌注损伤及其介导的肾脏炎症中发挥重要作用，肾脏巨噬细胞活化和炎症因子表达的分子调控机制是肾缺血再灌注损伤中重要的科学问题。申请人利用肾缺血再灌注小鼠疾病模型，通过系统筛选肾脏巨噬细胞基因表达谱改变，并重点关注在天然免疫和炎症中发挥重要调控作用的TRIM家族分子，发现肾脏巨噬细胞中TRIM27在肾缺血再灌注损伤后表达显著增高。据此，我们构建了条件型TRIM27基因敲除小鼠，并与LyzM-Cre巨噬细胞工具鼠杂交，获得了巨噬细胞特异性TRIM27敲除小鼠。我们发现，巨噬细胞特异性TRIM27敲除能够显著促进肾缺血再灌注损伤进展，肾脏炎症因子表达显著增高。由此，本工作拟探求肾脏巨噬细胞中TRIM27调控肾缺血再灌注损伤，尤其在调控肾脏炎症中的作用和机制，以期为移植肾缺血再灌注损伤提出新机制和干预新靶点。

肾脏巨噬细胞活化和炎症因子表达在移植肾缺血再灌注损伤及其介导的肾脏炎症中发挥重要作用，肾脏巨噬细胞活化和炎症因子表达的分子调控机制是肾缺血再灌注损伤中重要的科学问题。申请人利用肾缺血再灌注小鼠疾病模型，通过系统筛选肾脏巨噬细胞基因表达谱改变，发现肾脏巨噬细胞中TRIM27在肾缺血再灌注损伤后表达显著增高，提示肾脏巨噬细胞中TRIM27对于肾脏缺血再灌注损伤具有潜在调控作用。据此，我们构建了巨噬细胞特异性TRIM27敲除小鼠模型，利用此模型我们发现，巨噬细胞特异性TRIM27敲除能够显著促进肾缺血再灌注损伤进展，加重肾脏组织学及功能学损伤，促炎型巨噬细胞及中性粒细胞在肾脏组织中浸润增加，同时伴肾脏炎症因子表达显著增高。基于上述结果，我们进一步探求了肾脏巨噬细胞中TRIM27调控肾缺血再灌注损伤，尤其在调控肾脏炎症中的作用和机制，并重点关注TRIM27对巨噬细胞中TLR信号通路活化的调控机制，研究发现巨噬细胞TRIM27敲除对巨噬细胞TLR信号通路活化所诱导的关键下游信号通路NF-κB和MAPK活化具有关键性负向调控作用。综上，本研究结果提示，肾脏巨噬细胞TRIM27可通过负向调控巨噬细胞TLR信号通路活化所诱导的关键下游信号通路NF-κB和MAPK活化，从而减轻肾脏缺血再灌注损伤过程中由促炎型巨噬细胞所介导的炎症反应强度，进而改善小鼠肾脏缺血再灌注所致的组织学及功能学损伤，为移植肾缺血再灌注损伤提出新机制和干预新靶点。