Researchers highlight the central role of neutrophil extracellular traps in diabetic tissue repair, uncovering new therapeutic avenues to modulate inflammation and improve healing outcomes.
Researchers are increasingly treating neutrophil extracellular traps, or NETs, not as a single inflammatory by-product but as a central part of the biology of diabetic tissue repair. A review published in Wiley’s Biomedicine & Pharmacotherapy argues that these web-like structures, released by activated neutrophils, can either help clear infection or prolong the kind of sterile inflammation that derails healing in diabetes. The balance appears to depend on where the traps form, how many are produced and how long they persist.
The review says the diabetic wound environment encourages excessive NET formation through a mix of hyperglycaemia, oxidative stress, altered pH, mechanical strain and inflammatory signals. It describes how neutrophils respond to these cues by changing their metabolism, relying heavily on glycolysis and the pentose phosphate pathway to fuel NET release. That metabolic shift also appears to affect insulin resistance, immune cell behaviour and the local tissue environment, making NETs part of a wider cycle of inflammation and poor repair.
The paper also highlights the double-edged nature of NETs. At lower levels, they may help control bacteria and support early wound closure. At higher levels, they can damage extracellular matrix, injure endothelial cells, promote thrombosis and interfere with the migration and proliferation of cells needed for regeneration. In diabetic retinopathy, skeletal muscle repair, bone healing, vascular regeneration, skin ulcers, periodontal disease and nerve repair, the review finds that excessive NET activity is generally associated with worse outcomes, although the exact effect varies by tissue and concentration.
One of the review’s central points is that diabetic complications are not driven by NETs alone but by an entire inflammatory network. Neutrophil enzymes such as neutrophil elastase and myeloperoxidase, citrullinated histones, matrix metalloproteinases and signals from macrophages, endothelial cells and keratinocytes all contribute to the damage. The authors also note that certain molecular pathways, including PAD4, FOXM1, LRG1, TRPV1 and the NLRP3 inflammasome, appear to shape how much NET formation occurs and whether repair proceeds or stalls.
That has prompted interest in therapies that can modulate NETs rather than simply suppress inflammation. According to the review, conventional drugs such as metformin may reduce NET activity, but their usefulness is limited by delivery and overall therapeutic performance in complications such as atherosclerosis, retinopathy and ulcers. Exosome-based approaches are also discussed, although the authors say their regenerative effects remain restricted. Nanomaterials, by contrast, are presented as particularly promising because they could be designed to sense glucose, detect NET burden, remove inflammatory material and support the migration and differentiation of tissue cells across the full course of healing.
Disclaimer: This content is for informational purposes only and is not intended to be a substitute for professional medical judgment, advice, diagnosis, or treatment.
