Bcl-6-directed follicular helper T cells promote vascular inflammatory injury in diabetic retinopathy
Bcl-6-directed follicular helper T cells promote vascular inflammatory injury in diabetic retinopathy
复制标题
Bcl-6定向滤泡辅助T细胞促进糖尿病视网膜病变血管炎症损伤
DOI：
10.7150/thno.43731
复制
发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Liu, Xialin
中科院分区：
文献类型：
--
作者：
Liu, Yan;Yang, Ziqi;Liu, Xialin
糖尿病视网膜病变（diabetic retinopathy，DR）是一种以慢性视网膜微血管炎症为特征的糖尿病并发症。CD 4 + T细胞参与了视网膜血管炎症反应，但在此过程中T细胞介导的反应的具体亚群和机制仍不清楚。目的：探讨滤泡辅助性T细胞（Follicular Helper T，Tfh）在DR视网膜血管炎症中的作用。方法：采用流式细胞术检测DR患者外周血PD-1（+）CXCR 5（+）CD 4（+）Tfh细胞。建立链脲佐菌素（STZ）诱导的DR模型和氧诱导的视网膜病变（OIR）模型，腹腔注射Bcl-6抑制剂79-6抑制Tfh细胞。结果：Tfh细胞在DR患者的循环中扩增，在STZ诱导的DR小鼠和OIR小鼠的循环、淋巴结和视网膜组织中也增加。值得注意的是，Bcl-6（Tfh细胞发育的关键转录因子）的抑制阻止了Tfh细胞及其典型的IL-21细胞因子的上调，并改善了DR小鼠的血管渗漏或OIR小鼠的视网膜血管生成，表明Bcl-6定向的Tfh细胞可以促进血管炎症和血管生成。我们的研究结果表明，过量的Bcl-6定向的Tfh细胞代表了DR的一个未被认识的特征，并负责视网膜血管炎症和血管生成，为DR的新治疗方法提供了机会。
Diabetic retinopathy (DR) is a vision-threatening complication of diabetes mellitus characterized by chronic retinal microvascular inflammation. The involvement of CD4+ T cells in retinal vascular inflammation has been considered, but the specific subset and mechanism of T cell-mediated response during the process remains unclear. Here, we aim to investigate the potential role of follicular helper T (Tfh) cells, a newly identified subset of CD4+ T cells in retinal vascular inflammation in DR.Methods: Patients with DR were enrolled and the PD-1(+)CXCR5(+)CD4(+) Tfh cells were detected in the peripheral blood by flow cytometry. The streptozotocin (STZ)-induced DR model and oxygen-induced retinopathy (OIR) model were established, and 79-6, an inhibitor of Bcl-6, was injected intraperitoneally to suppress Tfh cells. The Tfh cells-related genes were investigated in the spleen, lymph nodes, and retina of mice by flow cytometry, immunofluorescence, and qPCR.Results: The Tfh cells expanded in the circulation of patients with DR and also increased in circulation, lymph nodes and retinal tissues from the STZ-induced DR mice and OIR mice. Notably, inhibition of Bcl-6, a critical transcription factor for Tfh cells development, prevented upregulation of Tfh cells and its typical IL-21 cytokine, and ameliorated vascular leakage in DR mice or retinal angiogenesis in OIR mice, indicating that Bcl-6-directed Tfh cells could promote vascular inflammation and angiogenesis.Conclusions: Our results suggested that excessive Bcl-6-directed Tfh cells represent an unrecognized feature of DR and be responsible for the retinal vascular inflammation and angiogenesis, providing opportunities for new therapeutic approaches to DR.