Ophthalmology and Visual Sciences, University of New Mexico, Albuquerque, NM.
New Mexico VA Health Care System, Albuquerque, NM.
Diabetes. 2023 Jun 1;72(6):781-794. doi: 10.2337/db22-0619.
Inflammation plays an important role in the pathogenesis of diabetic retinopathy (DR). To precisely define the inflammatory mediators, we examined the transcriptomic profile of human retinal endothelial cells exposed to advanced glycation end products, which revealed the neutrophil chemoattractant chemokine CXCL1 as one of the top genes upregulated. The effect of neutrophils in the alteration of the blood-retinal barrier (BRB) was further assessed in wild-type C57BL/6J mice intravitreally injected with recombinant CXCL1 as well as in streptozotocin-induced diabetic mice. Both intravitreally CXCL1-injected and diabetic animals showed significantly increased retinal vascular permeability, with significant increase in infiltration of neutrophils and monocytes in retinas and increased expression of chemokines and their receptors, proteases, and adhesion molecules. Treatment with Ly6G antibody for neutrophil depletion in both diabetic mice as well as CXCL1-injected animals showed significantly decreased retinal vascular permeability accompanied by decreased infiltration of neutrophils and monocytes and decreased expression of cytokines and proteases. CXCL1 level was significantly increased in the serum samples of patients with DR compared with samples of those without diabetes. These data reveal a novel mechanism by which the chemokine CXCL1, through neutrophil recruitment, alters the BRB in DR and, thus, serves as a potential novel therapeutic target.
Intravitreal CXCL1 injection and diabetes result in increased retinal vascular permeability with neutrophil and monocyte recruitment. Ly6G antibody treatment for neutrophil depletion in both animal models showed decreased retinal permeability and decreased cytokine expression. CXCL1 is produced by retinal endothelial cells, pericytes, and astrocytes. CXCL1 level is significantly increased in serum samples of patients with diabetic retinopathy. CXCL1, through neutrophil recruitment, alters the blood-retinal barrier in diabetic retinopathy and, thus, may be used as a therapeutic target.
炎症在糖尿病性视网膜病变（DR）的发病机制中起重要作用。为了精确定义炎症介质，我们检查了暴露于晚期糖基化终产物的人视网膜内皮细胞的转录组谱，该谱揭示中性粒细胞趋化因子趋化因子 CXCL1 是上调的顶级基因之一。进一步在野生型 C57BL/6J 小鼠中评估了中性粒细胞在改变血视网膜屏障（BRB）中的作用，这些小鼠通过重组 CXCL1 眼内注射以及链脲佐菌素诱导的糖尿病小鼠。眼内注射 CXCL1 和糖尿病动物的视网膜血管通透性均明显增加，视网膜中中性粒细胞和单核细胞浸润明显增加，趋化因子及其受体、蛋白酶和粘附分子的表达增加。在糖尿病小鼠和 CXCL1 注射动物中，用 Ly6G 抗体消耗中性粒细胞可显著降低视网膜血管通透性，同时减少中性粒细胞和单核细胞浸润，减少细胞因子和蛋白酶的表达。与无糖尿病患者的样本相比，DR 患者的血清样本中 CXCL1 水平显着升高。这些数据揭示了趋化因子 CXCL1 通过招募中性粒细胞改变 DR 中 BRB 的新机制，因此可作为一种潜在的新的治疗靶点。
