Diabetes primes neutrophils to undergo NETosis, which impairs wound healing
Open accessAbstract
Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.
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NETs contribute to etiology of some human pathologies including diabetes and cancer.
“NETs reportedly contribute to the etiology of some human pathologies, including diabetes and cancer [729–731].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [731]
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- Authors
- Wong, S. L., Demers, M., Martinod, K., Gallant, M., Wang, Y., Goldfine, A. B., Kahn, C. R., & Wagner, D. D.
- Affiliations
- Boston Children's Hospital (US)
- Pennsylvania State University (US)
- Joslin Diabetes Center (US)
- Corresponding author
- Wagner, Denisa D
- Venue
- Nature Medicine
- Published
- 2015-06-15
- Volume
- 21
- Issue
- 7
- Pages
- 815-819
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4631120
- OpenAlex
- W1913879859
- Cited by
- 1,264
- References
- 40
- Citations by year
- 2026: 151 · 2025: 156 · 2024: 131 · 2023: 146 · 2022: 138 · 2021: 141 · 2020: 104 · 2019: 81 · 2018: 76 · 2017: 64 · 2016: 59 · 2015: 14 · 2012: 1
- FWCI
- 35.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR001102)
- National Heart, Lung, and Blood Institute (R01HL102101, T32HL066987)
- National Cancer Institute (R01CA136856)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK031036, P30DK036836)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Epidemiology › Autoimmune and Inflammatory Disorders
- Keywords
- NETosis, neutrophils, wound healing, diabetes mellitus, PAD4, extracellular traps, citrullinated histone H3, DNase1, type 1 diabetes, type 2 diabetes, chronic inflammation, chromatin decondensation
- MeSH terms
- Protein-Arginine Deiminase Type 4, Adult, Animals, Blood Glucose, Deoxyribonuclease I, Diabetes Mellitus, Experimental, Female, Histones, Humans, Hydrolases, Male, Mice, Inbred C57BL, Middle Aged, Neutrophils, Time Factors, Wound Healing, Blotting, Western, Ionomycin, Young Adult, Extracellular Traps
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