Hyperglycemia Induces Neutrophil Extracellular Traps Formation Through an NADPH Oxidase-Dependent Pathway in Diabetic Retinopathy

Abstract

Neutrophil extracellular traps (NETs), the product of NETosis, is found to localize pathogens and crystals in immune response. Recent studies have found that excessive NETs lead to disease conditions such as diabetes and its complications like diabetic retinopathy (DR). However, the correlation between NETs and high glucose or DR remains unclear. Here, we found NETs level was significantly increased in the serum of diabetic patients, especially in proliferation diabetic retinopathy (PDR) patients. High glucose dramatically increased NETs production in diabetic individuals with time prolonging. The activation of NADPH oxidase was involved in the NETs process which is triggered by high glucose. Moreover, we verified the infiltration of neutrophils in the eyes and adhesion to vascular endothelial cells in diabetic rat models. NETs formation was observed in the vitreous bodies and retinas of diabetic individuals, which indicates NETs may play a role in the pathogenesis of diabetic retinopathy. Furthermore, anti-VEGF therapy downregulates NETs production indicating that NADPH oxidase-derived ROS may be another signaling pathway involved in anti-VEGF therapy.

Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update

“…In a case-control association study, dsDNA-histone complex and NE levels were significantly increased in patients with diabetic retinopathy compared with those without [55]. As a further proof of it, Wang et al reported that an increased NET formation was observed in the serum of T2D patients with diabetic retinopathy irrespective of the stage of the disease, with NE driving this trend [59].…”

“…As NET formation is likely to be associated with glucose-stimulated reactive oxygen species (ROS) production, it is possible that ROS have a direct effect on NET production. In fact, diphenyleneiodonium and apocynin, two inhibitors of NADPH oxidase, reduce NET formation in neutrophils exposed to high glucose stimulation [59]. Accordingly, the inhibition of NADPH oxidase markedly decreased the release of extracellular DNA compared to high glucose condition, thus suggesting that glucose-induced NET production might be dependent on NADPH oxidase [59].…”

The Dual Role of Antimicrobial Peptides in Autoimmunity

“…Besides, Nemeth et al showed by ELISA and reverse transcription quantitative PCR (RT-qPCR) increased levels of HNP1–3 in the plasma of T1D patients; however, similar increases were observed in type 2 diabetes (T2D) patients, suggesting that hyperglycemia may be responsible for such increases and, consequently, may only be a consequence of the disease and not a cause ( 82 ). Indeed, hyperglycemia was demonstrated in a diabetic rat model to promote NET formation ( 83 ). Importantly, these studies measured the circulating levels of AMPs in patients that may not reflect the levels in the pancreas.…”

The diabetic lung: An easy target for SARS‐CoV‐2?

“…Recently, Barnes et al suggested that COVID‐19, 8 just like hyperglycaemia, 9 might induce abnormal production of neutrophil extracellular traps (NETs). NETosis is a neutrophil‐specific strategy to kill extracellular pathogens, consisting in the release of a decondensed chromatin web beaded with granular antimicrobial enzymes 9 .…”