Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing. C16-ceramides generate pro-inflammatory/pro-apoptotic ceramide-rich platforms on endothelial surfaces. To geo-localize ceramide-rich platforms, we invented a three-dimensional confocal assay and showed that retinopathy-producing cytokines TNFα and IL-1β induce ceramide-rich platform formation on retinal endothelial cells within seconds, with volumes increasing 2-logs, yielding apoptotic death. Anti-ceramide antibodies abolish these events. Furthermore, intravitreal and systemic anti-ceramide antibodies protect from diabetic retinopathy in standardized rodent ischemia reperfusion and streptozotocin models. These data support (1) retinal endothelial ceramide as a diabetic retinopathy treatment target, (2) early-stage therapy of non-proliferative diabetic retinopathy to prevent progression, and (3) systemic diabetic retinopathy treatment; and they characterize diabetic retinopathy as a “ceramidopathy” reversible by anti-ceramide immunotherapy.

糖尿病视网膜病变是一种导致失明的微血管疾病。使用酸性鞘磷脂酶敲除小鼠，我们报道神经酰胺的生成对于糖尿病视网膜病变的发展至关重要。在这里，在患有增殖性糖尿病视网膜病变的患者中，我们发现玻璃体神经酰胺失衡，病理性长链 C16-神经酰胺增加，保护性极长链 C26-神经酰胺减少。 C16-神经酰胺在内皮表面产生富含促炎/促凋亡神经酰胺的平台。为了对富含神经酰胺的平台进行地理定位，我们发明了一种三维共聚焦测定，结果表明，产生视网膜病变的细胞因子 TNFα 和 IL-1β 在几秒钟内诱导视网膜内皮细胞上富含神经酰胺的平台形成，体积增加了 2 个对数，产生凋亡性死亡。抗神经酰胺抗体可以消除这些事件。此外，玻璃体内和全身抗神经酰胺抗体在标准化啮齿动物缺血再灌注和链脲佐菌素模型中可预防糖尿病视网膜病变。这些数据支持（1）视网膜内皮神经酰胺作为糖尿病视网膜病变的治疗靶点，（2）非增殖性糖尿病视网膜病变的早期治疗以预防进展，以及（3）全身性糖尿病视网膜病变治疗；他们将糖尿病视网膜病变描述为一种可通过抗神经酰胺免疫疗法逆转的“神经酰胺病变”。