Adenosine diphosphate contributes to wound healing in diabetic mice through P2Y₁and P2Y₁₂receptors activation

Abstract

Several studies have shown the importance of purinergic signaling in various inflammatory dis-eases. In diabetes mellitus, there is an increase in the activity of some nucleotidases suggesting that this signaling may be affected in the diabetic skin. Thus, the aim of our study was to inves-tigate the effect of ADP on wound healing in diabetic skin. Swis and C57BL/6 mice were pharmacologic induced to type 1 diabetes and submitted to a full-thickness excisional wound model to evaluate the effect of ADP as a topic treatment. Adenosine diphosphate accelerated cutaneous wound healing, improved the new tissue formation, and increased collagen deposit by positively modulating P2Y1 and P2Y12 and TGF-β production. In parallel, ADP reduced reactive oxygen species production and TNF-𝛼 levels, while increased IFNγ, IL-10 and IL-13 levels in the skin. Also, ADP induced the migration of neutrophils, eosinophils, mast cells, TCRγ4+, and TCRγ5+ cells while reduced Treg cells towards the lesion at day 7. In accordance, ADP increased the proliferation and migration of fibroblast, induced myofibroblast differentiation and keratinocyte proliferation in a P2Y12-dependent manner. We provide the first evidence of ADP acting as a potent mediator on skin wound resolution and a possible therapeutic approach for diabetic patients worldwide.

Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation

“…We thank Dr Isabela Ramos to kindly provide the pyrophosphate used in the in vivo wound healing experiment. This manuscript has been released as a preprint at BioRxiv ( 76 ).…”