title: Diabetes primes neutrophils to undergo NETosis, which impairs wound healing.
abstract: 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.
authors.affiliation: 1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Siu Ling
authors.initials: SL
authors.lastname: Wong
authors.affiliation: 1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Demers
authors.affiliation: 1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martinod
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Gallant
authors.affiliation: Center for Eukaryotic Gene Regulation, Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Section of Clinical Research, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Allison B
authors.initials: AB
authors.lastname: Goldfine
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.affiliation: 1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA. [3] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
mesh_terms: D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003850:Deoxyribonuclease I / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology*; D065206:Extracellular Traps / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000172:deficiency / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D000080002:Protein-Arginine Deiminase Type 4; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D006657:Histones; D015759:Ionomycin; D006867:Hydrolases; D003850:Deoxyribonuclease I; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse