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 proteins1. 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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We thank H. Ferris for advice on diabetes protocols; L. DeVita for selection of diabetic patients; P. Forbes (The Harvard Clinical and Translational Science Center, US National Institutes of Health (NIH) Award UL1 TR001102) for statistical advice; J.E. Cabral and S. Cifuni for valuable technical support; and L. Cowan for manuscript preparation assistance. This study was supported by the American Diabetes Association (Innovation Award 7-13-IN-44 to D.D.W.), the National Heart, Lung, and Blood Institute of the NIH (R01HL102101 to D.D.W.), the National Cancer Institute (R01CA136856 to Y.W.), the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK031036 to C.R.K.) and a GlaxoSmithKline/Immune Disease Institute Alliance Fellowship (S.L.W.).
The authors declare no competing financial interests.
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Wong, S., Demers, M., Martinod, K. et al. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat Med 21, 815–819 (2015). https://doi.org/10.1038/nm.3887
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