Emerging role of neutrophil extracellular traps in the complications of diabetes mellitus

Shafqat, Areez; Rab, Saleha Abdul; Ammar, Osama; Salameh, Sulaiman Al; Alkhudairi, Anas; Kashir, Junaid; Alkattan, Khaled; Yaqinuddin, Ahmed

doi:10.3389/fmed.2022.995993

Cited by 23 publications

(15 citation statements)

References 154 publications

(187 reference statements)

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“…Neutrophils are activated to release NETs to limit the spread of bacteria and kill pathogens, which is considered a protective mechanism. However, more and more evidence shows that excessive NETs can cause damage to the tissues 38 …”

Section: Programmed Cell Death and Diabetic Woundsmentioning

confidence: 99%

“…Furthermore, TLR9 is activated to release ROS, which induces the recruitment of more immune cells through the NLRP3 inflammasome‐dependent pathway to jointly mediate tissue damage 44 . The proteins released with NETs, such as NE and MMP, are thought to delay wound healing by disrupting the ECM 38 . The autocrine HMGB1 by keratinocytes is also thought to induce NETosis to impair wound healing 45 .…”

Section: Programmed Cell Death and Diabetic Woundsmentioning

confidence: 99%

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Neutrophils extracellular traps and ferroptosis in diabetic wounds

Huang

Ding

Wang

et al. 2023

International Wound Journal

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Wound healing is an extremely complex process involving multiple levels of cells and tissues. It is mainly completed through four stages: haemostasis, inflammation, proliferation, and remodelling. When any one of these stages is impaired, it may lead to delayed healing or even transformation into chronic refractory wounds. Diabetes is a kind of common metabolic disease that affects approximately 500 million people worldwide, 25% of whom develop skin ulcers that break down repeatedly and are difficult to heal, making it a growing public health problem. Neutrophils extracellular traps and ferroptosis are new types of programmed cell death identified in recent years and have been found to interact with diabetic wounds. In this paper, the normal wound healing and interfering factors of the diabetic refractory wound were outlined. The mechanism of two kinds of programmed cell death was also described, and the interaction mechanism between different types of programmed cell death and diabetic refractory wounds was discussed.

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Section: Programmed Cell Death and Diabetic Woundsmentioning

confidence: 99%

Section: Programmed Cell Death and Diabetic Woundsmentioning

confidence: 99%

Neutrophils extracellular traps and ferroptosis in diabetic wounds

Huang

Ding

Wang

et al. 2023

International Wound Journal

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“…Hyperglycemia has been shown to aggravate NETosis, indicating the significance of this event in the underlying aetiology of diabetes ( 40 ). We therefore wanted to measure NETosis in normoglycemic (5 mM = 4.8% HbA1c) and hyperglycemic (15 mM = 11% HbA1c) conditions.…”

Section: Resultsmentioning

confidence: 99%

Spontaneous NETosis in diabetes: A role of hyperglycemia mediated ROS and autophagy

et al. 2023

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Type 2-diabetes, particularly poorly controlled diabetes, is a risk factor for several infections such as lower respiratory tract and skin infections. Hyperglycemia, a characteristic downstream effect of poorly controlled diabetes, has been shown to impair the function of immune cells, in particular neutrophils. Several studies have demonstrated that hyperglycemia-mediated priming of NADPH oxidase results in subsequent elevated levels of reactive oxygen species (ROS). In healthy neutrophils, ROS plays an important role in pathogen killing by phagocytosis and by induction of Neutrophil Extracellular Traps (NETs). Given the key role of ROS in autophagy, phagocytosis and NETosis, the relationship between these pathways and the role of diabetes in the modulation of these pathways has not been explored previously. Therefore, our study aimed to understand the relationship between autophagy, phagocytosis and NETosis in diabetes. We hypothesized that hyperglycemia-associated oxidative stress alters the balance between phagocytosis and NETosis by modulating autophagy. Using whole blood samples from individuals with and without type 2-diabetes (in the presence and absence of hyperglycemia), we demonstrated that (i) hyperglycemia results in elevated levels of ROS in neutrophils from those with diabetes, (ii) elevated levels of ROS increase LCIII (a marker for autophagy) and downstream NETosis. (iii) Diabetes was also found to be associated with low levels of phagocytosis and phagocytic killing of S. pneumoniae. (iv) Blocking either NADPH oxidase or cellular pathways upstream of autophagy led to a significant reduction in NETosis. This study is the first to demonstrate the role of ROS in altering NETosis and phagocytosis by modulating autophagy in type 2-diabetes.

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“…In our previous study, P. gingivalis LPS, one of the classical virulence factors, was demonstrated to trigger the formation of NETs, which was critical in maintaining homeostasis in periodontal tissues (Chen et al, 2022). It has been shown that hyperglycaemic environments in vitro and in vivo induce the release of NETs (Shafqat et al, 2022). However, NET formation in microenvironment with high glucose and intense inflammation had not been clearly investigated.…”

Section: Discussionmentioning

confidence: 99%

Excessive neutrophil extracellular trap formation induced by Porphyromonas gingivalis lipopolysaccharide exacerbates inflammatory responses in high glucose microenvironment

Tong

Yue²,

Fu³

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionNeutrophil extracellular trap (NET) is a novel defense strategy of neutrophils and found to be induced by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) or high glucose. The aim of this study was to investigate the roles and mechanisms of NET formation in high glucose inflammatory microenvironment.MethodsNETs induced by 1 μg/ml P. gingivalis LPS and/or 25 mM glucose were visualized using a fluorescence microscopy and the levels of extracellular DNA were determined by a microplate reader. The bactericidal efficiency of NETs was assessed by quantifying the survival P. gingivalis in neutrophils. The levels of NLRP3 and IL-1β in THP-1 derived-macrophages, and the expressions of p-PKC βII, p-MEK1/2, p-ERK1/2, ORAI1 and ORAI2 in neutrophils were detected by Western blot. Moreover, levels of intracellular Ca2+ and reactive oxygen species (ROS) in neutrophils were explored by flow cytometry.ResultsP. gingivalis LPS enhanced the formation of NETs and increased the levels of extracellular DNA in high glucose microenvironment (p < 0.05). Compared with normal glucose inflammatory microenvironment, quantities of extra- and intracellular viable P. gingivalis in neutrophils exposed to NETs induced in high glucose inflammatory one were increased (p < 0.05) and the expressions of NLRP3 and IL-1β were dramatically increased in macrophages co-cultured with NETs from high glucose inflammatory microenvironment (p < 0.05). In addition, levels of ROS, intracellular Ca2+, p-PKC βII, p-MEK1/2, p-ERK1/2, ORAI1 and ORAI2 were increased in neutrophils stimulated with both high glucose and P. gingivalis LPS compared with the single stimulus groups (p < 0.05).DiscussionIn high glucose inflammatory microenvironment, formation of NETs was enhanced via oxidative stress, which failed to reverse the decreased bactericidal capacity in high glucose microenvironment, and instead aggravated the subsequent inflammatory responses.

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Emerging role of neutrophil extracellular traps in the complications of diabetes mellitus

Cited by 23 publications

References 154 publications

Neutrophils extracellular traps and ferroptosis in diabetic wounds

Neutrophils extracellular traps and ferroptosis in diabetic wounds

Spontaneous NETosis in diabetes: A role of hyperglycemia mediated ROS and autophagy

Excessive neutrophil extracellular trap formation induced by Porphyromonas gingivalis lipopolysaccharide exacerbates inflammatory responses in high glucose microenvironment

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