Diabetes primes neutrophils to undergo NETosis which severely impairs wound healing
By Siu Ling Wong, M. Demers, K. Martinod, M. Gallant, Yanming Wang, Allison B Goldfine, C. R. Kahn, Denisa D Wagner. Nature Medicine, 2015
1,090 citations recorded by the source corpus.
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.
Subfields: Immunology, Immunology and Allergy, Rehabilitation
View Paper: https://www.semanticscholar.org/paper/cf3ea863a1517987a0ba07117102993bc2b21963
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Citations in the corpus
- From CRP to IL-6 to IL-1: Moving Upstream To Identify Novel Targets for Atheroprotection (2016, background): “Diabetes mellitus, a major cardiovascular risk factor, has also been reported to prime neutrophils to undergo NETosis.90 The central role played by the inflammasome has made inhibition of the IL-1 pathway an attractive theoretical target for atheroprotection,3,91,92 and several agents that target IL”
- Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “As such, NETs are a putative therapeutic target for one of the main disabling complications of diabetes (197).”
- Cellular and molecular mechanisms of skin wound healing (2024, neutral): “For example, it has been shown that neutrophils of patients with diabetes release NETs more readily 100,101 , which could partly explain their delayed healing.”
- Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “Hence, neutrophils from diabetic patients (Wong et al., 2015) and from systemic lupus erythematosus (SLE) patients (Garcia-Romo et al., 2011; Villanueva et al., 2011) have been shown to be more prone to NET formation.”
- Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice (2018, background): “A growing body of evidence indicates a role for NETs, not just in infections but also in noninfectious inflammatory diseases (13), thrombosis (16, 17), and impaired wound healing in diabetes (18).”
- Vitamin C and Immune Function (2017, background): “However, in chronic, non-healing wounds, such as those observed in diabetics, the neutrophils persist and instead undergo necrotic cell death which can perpetuate the inflammatory response and hinder wound healing [109,110].”