Abstract
Diabetic retinopathy (DR) is an inflammatory and progressive vaso-occlusive disease resulting in angiogenesis. Galectin-1 is a hypoxia-induced angiogenic factor associated with cancer and proliferative DR. Here we reveal a significant upregulation of galectin-1 in eyes of DR patients along with progression of clinical stages beginning from the pre-ischemic, inflammatory stage with diabetic macular edema, but not in eyes with non-diabetic retinal vascular occlusions. As for its regulatory mechanism unrelated to hypoxia but selective to DR, in vitro galectin-1/LGALS1 expression was shown to increase after application to Müller glial cells with interleukin (IL)-1β, which was induced in monocyte-derived macrophages and microglial cells via toll-like receptor (TLR) 4 signaling stimulated by advanced glycation endproducts (AGE). In vivo inhibition of AGE generation with aminoguanidine, macrophage depletion with clodronate liposomes, and antibody-based blockade of Il-1β and Tlr4 attenuated diabetes-induced retinal Lgals1 expression in mice. Fibrovascular tissues from proliferative DR eyes were immunoreactive for AGE, TRL4 and IL-1β in macrophages, and IL-1β receptor-positive glial cells expressed galectin-1. Therefore, diabetes-induced retinal AGE accumulation was suggested to activate IL-1β-related inflammatory cues in macrophages followed by Müller cells, linking to galectin-1 upregulation in human DR with time. Our data highlight AGE-triggered inflammation as the DR-selective inducer of galectin-1.
Highlights
Diabetic retinopathy (DR) is the most common microvascular complication in patients with diabetes, and may have a debilitating impact on visual acuity, eventually leading to blindness
To further investigate the involvement of galectin-1 in the worsening course of DR, we performed enzyme-linked immunosorbent assay (ELISA) experiments to measure galectin-1 protein levels in aqueous humor samples collected from DR eyes with different clinical stages of Diabetic macular edema (DME), proliferative DR (PDR), and neovascular glaucoma (NVG) and from control eyes of non-diabetic, age-matched subjects with cataract (CAT) alone
The mean galectin-1 levels were still higher in eyes with DME than in those with retinal vein occlusions, showing a statistically significant difference compared to branch retinal vein occlusion (BRVO) and a nonsignificant tendency to central retinal vein occlusion (CRVO) (Fig. 1A)
Summary
Diabetic retinopathy (DR) is the most common microvascular complication in patients with diabetes, and may have a debilitating impact on visual acuity, eventually leading to blindness. Studies have shown that the pathogenesis of DR involves activation of leukocytes (e.g., monocytes, granulocytes and lymphocytes), sharing similarities with chronic inflammatory diseases[1,2]. Activated leukocytes secrete many growth factors and cytokines including vascular endothelial growth factor (VEGF), interleukin (IL)-1β, and interferon (IFN)-γ, and cause retinal microvascular injury and leakage, suggesting that inflammation plays a significant role in the onset and progression of DR, especially at the pre-ischemic stage of DME3–7. Vitreous aspirates from eyes with PDR showed higher protein levels of galectin-1 than those from non-diabetic controls[15]. We investigated protein levels of galectin-1 in eyes with the different clinical stages of DR, and explored upstream regulatory stimuli for hypoxia-unrelated galectin-1 expression selectively in the pathogenesis of DR but not non-diabetic retinal vascular occlusions
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