循环髓系来源细胞中的 STAT3 激活导致糖尿病视网膜微血管功能障碍。
STAT3 activation in circulating myeloid-derived cells contributes to retinal microvascular dysfunction in diabetes.
机构信息
Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK.
Current address: Biomedical Sciences Research Institute, Ulster University, Coleraine, UK.
出版信息
J Neuroinflammation. 2019 Jul 8;16(1):138. doi: 10.1186/s12974-019-1533-1.
BACKGROUND
Leukostasis is a key patho-physiological event responsible for capillary occlusion in diabetic retinopathy. Circulating monocytes are the main cell type entrapped in retinal vessels in diabetes. In this study, we investigated the role of the signal transducer and activator of transcription 3 (STAT3) pathway in diabetes-induced immune cell activation and its contribution to retinal microvascular degeneration.
METHODS
Forty-one patients with type 1 diabetes (T1D) [mild non-proliferative diabetic retinopathy (mNPDR) (n = 13), active proliferative DR (aPDR) (n = 14), inactive PDR (iPDR) (n = 14)] and 13 age- and gender-matched healthy controls were recruited to the study. C57BL/6 J WT mice, SOCS3 and LysMSOCS3 mice were rendered diabetic by Streptozotocin injection. The expression of the phosphorylated human and mouse STAT3 (pSTAT3), mouse LFA-1, CD62L, CD11b and MHC-II in circulating immune cells was evaluated by flow cytometry. The expression of suppressor of cytokine signalling 3 (SOCS3) was examined by real-time RT-PCR. Mouse plasma levels of cytokines were measured by Cytometric Beads Array assay. Retinal leukostasis was examined following FITC-Concanavalin A perfusion and acellular capillary was examined following Isolectin B4 and Collagen IV staining.
RESULTS
Compared to healthy controls, the expression of pSTAT3 in circulating leukocytes was statistically significantly higher in mNPDR but not aPDR and was negatively correlated with diabetes duration. The expression of pSTAT3 and its inhibitor SOCS3 was also significantly increased in leukocytes from diabetic mice. Diabetic mice had higher plasma levels of IL6 and CCL2 compared with control mice. LysMSOCS3 mice and SOCS3 mice developed comparative levels of diabetes, but leukocyte activation, retinal leukostasis and number of acellular capillaries were statistically significantly increased in LysMSOCS3 diabetic mice.
CONCLUSION
STAT3 activation in circulating immune cells appears to contribute to retinal microvascular degeneration and may be involved in DR initiation in T1D.
背景
白细胞淤滞是导致糖尿病性视网膜病变毛细血管阻塞的关键病理生理事件。循环中的单核细胞是糖尿病患者视网膜血管中主要的被困细胞类型。在这项研究中，我们研究了信号转导和转录激活因子 3（STAT3）通路在糖尿病引起的免疫细胞激活中的作用及其对视网膜微血管退化的贡献。
方法
招募了 41 名 1 型糖尿病（T1D）患者（轻度非增生性糖尿病视网膜病变（mNPDR）（n=13）、活跃性增生性 DR（aPDR）（n=14）、静止性 PDR（iPDR）（n=14））和 13 名年龄和性别匹配的健康对照者。通过链脲佐菌素注射使 C57BL/6J WT 小鼠、SOCS3 和 LysMSOCS3 小鼠发生糖尿病。通过流式细胞术评估循环免疫细胞中磷酸化的人源和鼠源 STAT3（pSTAT3）、鼠源 LFA-1、CD62L、CD11b 和 MHC-II 的表达。通过实时 RT-PCR 检测抑制细胞因子信号转导 3（SOCS3）的表达。通过 Cytometric Beads Array 测定法测量鼠血浆细胞因子水平。通过 FITC-刀豆球蛋白 A 灌注检查视网膜白细胞淤滞，通过异硫氰酸荧光素标记的荆豆凝集素 B4 和胶原 IV 染色检查无细胞毛细血管。
结果
与健康对照组相比，mNPDR 患者循环白细胞中 pSTAT3 的表达显著升高，但 aPDR 患者中 pSTAT3 的表达没有升高，且与糖尿病病程呈负相关。糖尿病小鼠白细胞中 pSTAT3 及其抑制剂 SOCS3 的表达也显著增加。与对照组相比，糖尿病小鼠的血浆 IL6 和 CCL2 水平更高。与对照组相比，LysMSOCS3 糖尿病小鼠和 SOCS3 糖尿病小鼠的糖尿病发病程度相当，但 LysMSOCS3 糖尿病小鼠的白细胞活化、视网膜白细胞淤滞和无细胞毛细血管数量显著增加。
结论
循环免疫细胞中 STAT3 的激活似乎导致视网膜微血管退化，并可能参与 T1D 中 DR 的发生。
Zotero 插件