HMGB1-TLR4-IL-17A信号途径调控嗜中性粒细胞活化在肾缺血再灌注损伤中的作用及机制研究

Renal ischemia reperfusion injury (IRI) is a main cause of acute kidney injury (AKI). Both innate and adaptive immune responses play a central role in mediating renal injury. Local neutrophil recruitment and activation are crucial in the pathogenesis of renal IRI that occurs after renal ischemic. However, the mechanisms that drive the activation and infiltration of neutrophil in renal IRI remain unclear. Accumulating data demonstrate that high-mobility group box-1 protein (HMGB1) plays an important role in the regulating immune responses in renal IRI and directly affects the occurrence and development of AKI. Our pervious study has found that there is up regulation on the secretion of HMGB1 in the early stage of renal IRI. And we also found that HMGB1 played an important role in regulating the expression of surface molecules on macrophages and activation of macrophages and lymphocytes. Furthermore, HMGB1 also played an important role in regulating production of IL-23 and IL-17A, which directly affected the renal pathological injury. Therefore, we study on the immunoregulation mechanism of renal IRI. We focus on the extracellular “danger-signal molecule” HMGB1 in renal IRI. We observe the effect of IL-17A on regulating activation and infiltration of neutrophil in renal IRI and the effect of IL-17A production by IL-23 and the effect of HMGB1 on IL-23 production by macrophages via TLR4. We aim to clarify pathogenic mechanism of HMGB1 on regulating the interaction between immune cells and inflammatory cytokines in renal IRI.

肾缺血再灌注损伤（IRI）是导致急性肾损伤(AKI) 的主要原因。天然免疫应答在早期肾IRI中起着关键性的作用，而嗜中性粒细胞的募集活化是其重要环节。研究表明高迁移率族蛋白B1（HMGB1）在调控肾IRI的免疫炎症反应中具有重大意义，直接影响AKI的发生、发展。我们既往的研究发现肾脏缺血早期HMGB1释放增加，可上调巨噬细胞表面分子表达，促进巨噬细胞、淋巴细胞活化，增加IL-23、IL-17A分泌，诱导嗜中性粒细胞的浸润增加，直接影响肾组织损伤程度。因此，本课题在肾脏IRI的免疫学调节机制下，以肾IRI早期释放的内源性“危险信号分子” HMGB1为切入点，研究HMGB1在肾IRI中通过巨噬细胞TLR4受体途径调节IL-23的分泌，促进特异性淋巴细胞产生IL-17A进而调控嗜中性粒细胞活化，引起肾组织损伤的致病机理。

肾缺血再灌注损伤（IRI）是急性肾功能衰竭最常见的病因，病情危重，预后较差。自身免疫反应在IRI中发挥重要作用，寻找免疫反应起始点。对研究IRI具有重要意义。核内蛋白HMGB1在肾缺血时即从受损细胞释放至胞外激活炎症反应而导致急性肾损伤，阻断HMGB1释放能显著抑制炎症反应，减轻急性肾损伤；可见HMGB1即期配体TLR4信号通路在自身免疫反应启动中发挥重要作用。研究表明HMGB-TLR4信号通路可在DC细胞调节IL-23的分泌，IL-23可促进淋巴细胞分泌IL-17A,而IL-17A在IRI具有极其重要的致炎作用。本研究成功构建小鼠缺血再灌注模型，以肾IRI早期释放的内源性“危险信号分子” HMGB1为切入点，分别阻断HMGB1的表达或通过HMGB1重组蛋白的作用，研究HMGB1在肾IRI中通过巨噬细胞TLR4受体途径调节IL-23的分泌，促进特异性淋巴细胞产生IL-17A进而调控嗜中性粒细胞活化，引起肾组织损伤的致病机理，为选择新的药物靶点提供策略。