Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States.
Invest Ophthalmol Vis Sci. 2023 Jun 1;64(7):17. doi: 10.1167/iovs.64.7.17.
CD40 is upregulated in the retinas of diabetic mice, drives pro-inflammatory molecule expression, and promotes diabetic retinopathy. The role of CD40 in diabetic retinopathy in humans is unknown. Upregulation of CD40 and its downstream signaling molecules TNF receptor associated factors (TRAFs) is a key feature of CD40-driven inflammatory disorders. We examined the expression of CD40, TRAF2, and TRAF6 as well as pro-inflammatory molecules in retinas from patients with diabetic retinopathy.
Posterior poles from patients with diabetic retinopathy and non-diabetic controls were stained with antibodies against von Willebrand factor (labels endothelial cells), cellular retinaldehyde-binding protein (CRALBP), or vimentin (both label Müller cells) plus antibodies against CD40, TRAF2, TRAF6, ICAM-1, CCL2, TNF-α, and/or phospho-Tyr783 phospholipase Cγ1 (PLCγ1). Sections were analyzed by confocal microscopy.
CD40 expression was increased in endothelial and Müller cells from patients with diabetic retinopathy. CD40 was co-expressed with ICAM-1 in endothelial cells and with CCL2 in Müller cells. TNF-α was detected in retinal cells from these patients, but these cells lacked endothelial/Müller cell markers. CD40 in Müller cells from patients with diabetic retinopathy co-expressed activated phospholipase Cγ1, a molecule that induces TNF-α expression in myeloid cells in mice. CD40 upregulation in endothelial cells and Müller cells from patients with diabetic retinopathy was accompanied by TRAF2 and TRAF6 upregulation.
CD40, TRAF2, and TRAF6 are upregulated in patients with diabetic retinopathy. CD40 associates with expression of pro-inflammatory molecules. These findings suggest that CD40-TRAF signaling may promote pro-inflammatory responses in the retinas of patients with diabetic retinopathy.
CD40 在糖尿病小鼠的视网膜中上调，驱动促炎分子的表达，并促进糖尿病性视网膜病变。CD40 在人类糖尿病性视网膜病变中的作用尚不清楚。CD40 及其下游信号分子 TNF 受体相关因子（TRAFs）的上调是 CD40 驱动的炎症性疾病的一个关键特征。我们检查了 CD40、TRAF2 和 TRAF6 以及促炎分子在糖尿病性视网膜病变患者视网膜中的表达。
用针对血管性血友病因子（标记内皮细胞）、细胞视黄醛结合蛋白（CRALBP）或波形蛋白（均标记 Müller 细胞）的抗体以及针对 CD40、TRAF2、TRAF6、ICAM-1、CCL2、TNF-α和/或磷酸化 Tyr783 磷脂酶 Cγ1（PLCγ1）的抗体对来自糖尿病性视网膜病变患者和非糖尿病对照者的后极进行染色。通过共聚焦显微镜分析切片。
CD40 在来自糖尿病性视网膜病变患者的内皮细胞和 Müller 细胞中的表达增加。CD40 与内皮细胞中的 ICAM-1 和 Müller 细胞中的 CCL2 共表达。这些患者的视网膜细胞中检测到 TNF-α，但这些细胞缺乏内皮/ Müller 细胞标志物。来自糖尿病性视网膜病变患者的 Müller 细胞中的 CD40 与激活的磷脂酶 Cγ1 共表达，该分子在小鼠的髓样细胞中诱导 TNF-α表达。来自糖尿病性视网膜病变患者的内皮细胞和 Müller 细胞中 CD40 的上调伴随着 TRAF2 和 TRAF6 的上调。
CD40、TRAF2 和 TRAF6 在糖尿病性视网膜病变患者中上调。CD40 与促炎分子的表达相关。这些发现表明 CD40-TRAF 信号可能促进糖尿病性视网膜病变患者视网膜中的促炎反应。
