美国密歇根州立大学Julia V. Busik和Richard N. Kolesnick研究组取得一项新突破。他们发现了糖尿病视网膜病变是一种神经系统病变，可通过抗神经酰胺免疫治疗逆转。相关论文于2024年5月7日发表在《细胞—代谢》杂志上。

使用酸性鞘磷脂酶敲除小鼠，研究小组报道神经酰胺的产生对糖尿病视网膜病变的发展至关重要。在增殖性糖尿病视网膜病变患者中，课题组发现玻璃体神经酰胺失衡，病理性长链C16-神经酰胺增加，保护性长链C26-神经酰胺减少。C16-神经酰胺在内皮表面产生促炎/促凋亡的富含神经酰胺的平台。

为了定位富含神经酰胺的平台，研究团队发明了一种三维共聚焦实验，结果表明，视网膜病变产生的细胞因子TNFα和IL-1β在几秒钟内诱导视网膜内皮细胞形成富含神经酰胺的平台，体积增加2倍，导致细胞凋亡。抗神经酰胺抗体消除这些事件。

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，保护糖尿病视网膜病变。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防止进展，以及(3)全身性糖尿病视网膜病变的治疗，他们将糖尿病视网膜病变定性为一种“神经病变”，可通过抗神经酰胺免疫治疗逆转。

附：英文原文

Title: Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy

Author: Tim F. Dorweiler, Arjun Singh, Aditya Ganju, Todd A. Lydic, Louis C. Glazer, Richard N. Kolesnick, Julia V. Busik

Issue&Volume: 2024-05-07

Abstract: 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.

DOI: 10.1016/j.cmet.2024.04.013

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00133-5