The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.
NETosis Delays Diabetic Wound Healing in Mice and Humans
Abstract
Upon activation, neutrophils undergo histone citrullination by protein arginine deiminase (PAD)4, exocytosis of chromatin and enzymes as neutrophil extracellular traps (NETs), and death. In diabetes, neutrophils are primed to release NETs and die by NETosis. Although this process is a defense against infection, NETosis can damage tissue. Therefore, we examined the effect of NETosis on the healing of diabetic foot ulcers (DFUs). Using proteomics, we found that NET components were enriched in nonhealing human DFUs. In an independent validation cohort, a high concentration of neutrophil elastase in the wound was associated with infection and a subsequent worsening of the ulcer. NET components (elastase, histones, neutrophil gelatinase-associated lipocalin, and proteinase-3) were elevated in the blood of patients with DFUs. Circulating elastase and proteinase-3 were associated with infection, and serum elastase predicted delayed healing. Neutrophils isolated from the blood of DFU patients showed an increased spontaneous NETosis but an impaired inducible NETosis. In mice, skin PAD4 activity was increased by diabetes, and FACS detection of histone citrullination, together with intravital microscopy, showed that NETosis occurred in the bed of excisional wounds. PAD4 inhibition by Cl-amidine reduced NETting neutrophils and rescued wound healing in diabetic mice. Cumulatively, these data suggest that NETosis delays DFU healing.
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Cites
Neutrophil Extracellular Traps Kill Bacteria
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Cellular and molecular basis of wound healing in diabetes
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Inflammatory cells during wound repair: the good, the bad and the ugly
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“Inflammation is a typical feature of the wound healing process, and neutrophils are recruited early to the wound bed (3).”
BackgroundDiabetes primes neutrophils to undergo NETosis, which impairs wound healing
Wong, S. L., Demers, M., Martinod, K., Gallant, M., Wang, Y., Goldfine, A. B., Kahn, C. R., & Wagner, D. D. (2015) · Nature Medicine · doi:10.1038/nm.3887 · Cited by 1,264
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Pilsczek, F. H., Salina, D., Poon, K. K. H., Fahey, C., Yipp, B. G., Sibley, C. D., Robbins, S. M., Green, F. H. Y., Surette, M. G., Sugai, M., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000675 · Cited by 1,114
Incidence, outcomes, and cost of foot ulcers in patients with diabetes.
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Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality
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Accelerated wound closure in neutrophil-depleted mice
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Cited by
An emerging role for neutrophil extracellular traps in noninfectious disease
Jorch, S. K., & Kubes, P. (2017) · Nature Medicine · doi:10.1038/nm.4294 · Cited by 1,244
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Neutrophil Extracellular Trap Formation: Physiology, Pathology, and Pharmacology
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Metadata
- Authors
- Fadini, G. P., Menegazzo, L., Rigato, M., Scattolini, V., Poncina, N., Bruttocao, A., Ciciliot, S., Mammano, F., Ciubotaru, C. D., Brocco, E., Marescotti, M. C., Cappellari, R., Arrigoni, G., Millioni, R., Vigili de Kreutzenberg, S., Albiero, M., & Avogaro, A.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-01-06
- Volume
- 65
- Issue
- 4
- Pages
- 1061-1071
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2254774777
- Cited by
- 339
- References
- 24
- FWCI
- 14.81
- Type
- journal article
- Language
- en
- Open access
- closed
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- Fadini, G. P., Menegazzo, L., Rigato, M., Scattolini, V., Poncina, N., Bruttocao, A., Ciciliot, S., Mammano, F., Ciubotaru, C. D., Brocco, E., Marescotti, M. C., Cappellari, R., Arrigoni, G., Millioni, R., Vigili de Kreutzenberg, S., Albiero, M., & Avogaro, A. (2016). NETosis Delays Diabetic Wound Healing in Mice and Humans. Diabetes. https://doi.org/10.2337/db15-0863
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