肾小管源性STING诱导B淋巴细胞浸润促进肾间质纤维化的作用及机制研究

Renal interstitial fibrosis is the significant pathological basis of chronic kidney disease, and B lymphocyte infiltration plays a crucial role in the development of renal interstitial fibrosis. However, the mechanisms of B lymphocytes infiltration in renal fibrosis remain unclear. Stimulator of Interferon Genes (STING)is an important molecule inducing immune cell migration. Our previous studies showed that STING is significantly increased in fibrotic kidney, accompanied with chemokine CX3CL1 activation and increased B lymphocytes infiltration. In contrast, STING knockdown significantly ameliorates renal fibrosis and B lymphocyte infiltration. Thus, it is supposed that renal tubular-derived STING may promote renal fibrosis by inducing the B lymphocyte infiltration, which may be associated with the activation of CX3CL1. Therefore, we plan to choose HK-2 cells, B lymphocytes and STING-/- mice as the object of study in this research, and we can further discuss the mechanisms of tubular-derived STING induces the B lymphocyte infiltration in renal interstitial fibrosis. This project can not only clarify the role of tubular-derived STING in renal interstitial fibrosis, but also elucidate the mechanisms of STING induced-B-lymphocyte infiltration through increasing CX3CL1 expression. The purpose of this study provides us new idea to reveal the development of renal fibrosis and find the control measures.

肾间质纤维化(RIF)是慢性肾脏病主要的病理改变，B淋巴细胞浸润是其发生发展的一个突出诱因，但诱导肾间质B淋巴细胞浸润的机制不清。干扰素刺激因子（STING）是一种能够诱导免疫细胞发生迁移的重要分子。我们前期研究发现纤维化肾组织中STING、CX3CL1表达明显增高，同时伴随B淋巴细胞浸润增加，而STING敲除鼠RIF明显减轻、B淋巴细胞浸润减少。故推测“肾小管源性STING可能通过上调CX3CL1的表达，诱导B淋巴细胞浸润，进而促进RIF”。本课题拟以HK-2细胞、B淋巴细胞及STING-/-小鼠为研究对象，探讨肾小管源性STING诱导B淋巴细胞浸润促进RIF的具体机制。该项目不仅能明确肾小管源性STING在RIF中的作用,还有望阐明肾小管源性STING通过上调CX3CL1诱导B淋巴细胞在肾间质浸润的新机制，为揭示RIF持续进展的机制及寻找防治措施提供新思路。

肾纤维化是慢性肾脏病发生发展的共同病理特征，但导致肾纤维化的机制未完全阐明。多种因素参与了肾纤维化的进展，研究表明免疫细胞也在肾纤维化中发挥着重要作用。本研究在CKD患者的肾脏标本中发现CD19+及CD38+B淋巴细胞浸润，Spearman相关分析结果显示CKD患者eGFR与肾纤维化呈正相关，eGFR与CD20+或CD38+阳性的B细胞负相关。在进一步的研究中，我们发现B淋巴细胞在缺血再灌注损伤模型小鼠肾脏中浸润，在AKI转变为慢性肾脏病的过程中发生定植，从而促进肾纤维化的发生。然而，与野生型小鼠相比，aCD20抗体治疗的小鼠的梗阻肾脏CD19+B淋巴细胞浸润减少、胶原沉积减轻。因此，我们的研究证实了B淋巴细胞参与肾纤维化发生发展的机理，为CKD的治疗提供了新的靶点。