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

Luoziyi Wang,Yuxin Mai,Xin Zhou,Yizhou Yin,Desai Wang,Xuedong Zhang

doi:10.3389/fimmu.2018.03076

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.

Highlights

Diabetes mellitus (DM) is one of the most common metabolic disorders in both developing and developed countries [1, 2]
The results showed that Neutrophil extracellular traps (NETs) formation was obviously elevated in type 2 diabetes mellitus (T2DM) patients in the presence or absence of diabetic retinopathy (DR) (Figure 1A)
It was proved that serum neutrophil elastase (NE) level was higher in diabetes without retinopathy (DWR), non-proliferative phase of DR (NPDR), and proliferation diabetic retinopathy (PDR) groups when compared with healthy controls, respectively (Figure 1D)

Summary

Introduction

Diabetes mellitus (DM) is one of the most common metabolic disorders in both developing and developed countries [1, 2]. The epidemiological data showed that it is affecting 1 in 10 people all over the world. It was estimated by the World Health Organization (WHO) that the number of people living with this disease will reach 366 million by 2030 [3]. The International Diabetes Federation (IDF) reported that the number will reach 693 million by 2045 [4, 5]. High circulating sugar/glucose in the blood can influence cellular functions and attack macro- and microvessels throughout the whole organs [3]. IDF announced that there are almost 5 million people dying from diabetes-specific complications such as retinopathy and nephropathy than high-risk infectious diseases such as AIDS and tuberculosis [6]

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