Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation
Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.651740/full |
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| author | Paula Alvarenga Borges Paula Alvarenga Borges Ingrid Waclawiak Janaína Lima Georgii Vanderlei da Silva Fraga-Junior Janaína Figueiredo Barros Felipe Simões Lemos Thaís Russo-Abrahão Elvira Maria Saraiva Christina M. Takiya Robson Coutinho-Silva Carmen Penido Carmen Penido Claudia Mermelstein José Roberto Meyer-Fernandes Fábio B. Canto Josiane Sabbadini Neves Paulo A. Melo Claudio Canetti Claudia Farias Benjamim Claudia Farias Benjamim |
| author_facet | Paula Alvarenga Borges Paula Alvarenga Borges Ingrid Waclawiak Janaína Lima Georgii Vanderlei da Silva Fraga-Junior Janaína Figueiredo Barros Felipe Simões Lemos Thaís Russo-Abrahão Elvira Maria Saraiva Christina M. Takiya Robson Coutinho-Silva Carmen Penido Carmen Penido Claudia Mermelstein José Roberto Meyer-Fernandes Fábio B. Canto Josiane Sabbadini Neves Paulo A. Melo Claudio Canetti Claudia Farias Benjamim Claudia Farias Benjamim |
| author_sort | Paula Alvarenga Borges |
| collection | DOAJ |
| description | Chronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5’-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y12 receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y12 receptor antagonist. Furthermore, P2Y1 receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y12 and P2Y1 receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4+ and Vγ5+ cells subtypes of γδ+ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem. |
| first_indexed | 2024-12-22T06:12:18Z |
| format | Article |
| id | doaj.art-05ea3e3283e24c8abf88a07d23bfa717 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-22T06:12:18Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-05ea3e3283e24c8abf88a07d23bfa7172022-12-21T18:36:11ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.651740651740Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor ActivationPaula Alvarenga Borges0Paula Alvarenga Borges1Ingrid Waclawiak2Janaína Lima Georgii3Vanderlei da Silva Fraga-Junior4Janaína Figueiredo Barros5Felipe Simões Lemos6Thaís Russo-Abrahão7Elvira Maria Saraiva8Christina M. Takiya9Robson Coutinho-Silva10Carmen Penido11Carmen Penido12Claudia Mermelstein13José Roberto Meyer-Fernandes14Fábio B. Canto15Josiane Sabbadini Neves16Paulo A. Melo17Claudio Canetti18Claudia Farias Benjamim19Claudia Farias Benjamim20Institute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilFluminense Federal Institute (IFF), Rio de Janeiro, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Medical Biochemistry Leopoldo de Meis, Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilInstitute of Microbiology Paulo de Góes, Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilInstitute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilInstitute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilCenter for Technological Development in Health, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilLaboratory of Applied Pharmacology, Institute of Drug Technology, Farmanguinhos, Oswaldo Cruz Foundation, Rio de Janeiro, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Medical Biochemistry Leopoldo de Meis, Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilDepartment of Immunobiology, Institute of Biology, Fluminense Federal University (UFF), Niterói, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilInstitute of Biomedical Sciences, Center of Health Sciences, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilInstitute of Biophysics Carlos Chagas Filho (IBCCF), Center of Health Sciences, UFRJ, Rio de Janeiro, BrazilChronic wounds are a public health problem worldwide, especially those related to diabetes. Besides being an enormous burden to patients, it challenges wound care professionals and causes a great financial cost to health system. Considering the absence of effective treatments for chronic wounds, our aim was to better understand the pathophysiology of tissue repair in diabetes in order to find alternative strategies to accelerate wound healing. Nucleotides have been described as extracellular signaling molecules in different inflammatory processes, including tissue repair. Adenosine-5’-diphosphate (ADP) plays important roles in vascular and cellular response and is immediately released after tissue injury, mainly from platelets. However, despite the well described effect on platelet aggregation during inflammation and injury, little is known about the role of ADP on the multiple steps of tissue repair, particularly in skin wounds. Therefore, we used the full-thickness excisional wound model to evaluate the effect of local ADP application in wounds of diabetic mice. ADP accelerated cutaneous wound healing, improved new tissue formation, and increased both collagen deposition and transforming growth factor-β (TGF-β) production in the wound. These effects were mediated by P2Y12 receptor activation since they were inhibited by Clopidogrel (Clop) treatment, a P2Y12 receptor antagonist. Furthermore, P2Y1 receptor antagonist also blocked ADP-induced wound closure until day 7, suggesting its involvement early in repair process. Interestingly, ADP treatment increased the expression of P2Y12 and P2Y1 receptors in the wound. In parallel, ADP reduced reactive oxygen species (ROS) formation and tumor necrosis factor-α (TNF-α) levels, while increased IL-13 levels in the skin. Also, ADP increased the counts of neutrophils, eosinophils, mast cells, and gamma delta (γδ) T cells (Vγ4+ and Vγ5+ cells subtypes of γδ+ T cells), although reduced regulatory T (Tregs) cells in the lesion. In accordance, ADP increased fibroblast proliferation and migration, myofibroblast differentiation, and keratinocyte proliferation. In conclusion, we provide strong evidence that ADP acts as a pro-resolution mediator in diabetes-associated skin wounds and is a promising intervention target for this worldwide problem.https://www.frontiersin.org/articles/10.3389/fimmu.2021.651740/fulladenosine diphosphate (ADP)wound healingmiceskindiabetesinflammation |
| spellingShingle | Paula Alvarenga Borges Paula Alvarenga Borges Ingrid Waclawiak Janaína Lima Georgii Vanderlei da Silva Fraga-Junior Janaína Figueiredo Barros Felipe Simões Lemos Thaís Russo-Abrahão Elvira Maria Saraiva Christina M. Takiya Robson Coutinho-Silva Carmen Penido Carmen Penido Claudia Mermelstein José Roberto Meyer-Fernandes Fábio B. Canto Josiane Sabbadini Neves Paulo A. Melo Claudio Canetti Claudia Farias Benjamim Claudia Farias Benjamim Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation Frontiers in Immunology adenosine diphosphate (ADP) wound healing mice skin diabetes inflammation |
| title | Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation |
| title_full | Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation |
| title_fullStr | Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation |
| title_full_unstemmed | Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation |
| title_short | Adenosine Diphosphate Improves Wound Healing in Diabetic Mice Through P2Y12 Receptor Activation |
| title_sort | adenosine diphosphate improves wound healing in diabetic mice through p2y12 receptor activation |
| topic | adenosine diphosphate (ADP) wound healing mice skin diabetes inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.651740/full |
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