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. 2016 Apr;65(4):1061-71.
doi: 10.2337/db15-0863. Epub 2016 Jan 6.

NETosis Delays Diabetic Wound Healing in Mice and Humans

Gian Paolo Fadini  1 , Lisa Menegazzo  2 , Mauro Rigato  3 , Valentina Scattolini  2 , Nicol Poncina  2 , Andrea Bruttocao  3 , Stefano Ciciliot  2 , Fabio Mammano  4 , Catalin Dacian Ciubotaru  5 , Enrico Brocco  6 , Maria Cristina Marescotti  3 , Roberta Cappellari  3 , Giorgio Arrigoni  7 , Renato Millioni  8 , Saula Vigili de Kreutzenberg  3 , Mattia Albiero  2 , Angelo Avogaro  2
Affiliations

NETosis Delays Diabetic Wound Healing in Mice and Humans

Gian Paolo Fadini et al. Diabetes. 2016 Apr.

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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