Jararhagin-C, a disintegrin-like protein, improves wound healing in mice through stimulation of M2-like macrophage, angiogenesis and collagen deposition

• Published in: International immunopharmacology Vol. 101; no. Pt B; p. 108224
• Main Authors: Ferreira, Bruno Antonio, De Moura, Francyelle Borges Rosa, Tomiosso, Tatiana Carla, Corrêa, Natássia Caroline Resende, Goulart, Luiz Ricardo, Barcelos, Lucíola Silva, Clissa, Patrícia Bianca, Araújo, Fernanda de Assis
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-12-2021; Elsevier BV
• Subjects: Angiogenesis; Animals; Blood vessels; Bothrops jararaca Venom; Cell Survival - drug effects; Collagen; Collagen - metabolism; Crotalid Venoms - chemistry; Cytokines; Cytokines - genetics; Cytokines - metabolism; Deposition; Disintegrin; Disintegrins - chemistry; Disintegrins - pharmacology; Fibroblast growth factors; Fibrogenesis; Gene expression; Gene Expression Regulation - drug effects; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Leukocytes (neutrophilic); Leukocytes - drug effects; Leukocytes - physiology; Macrophage polarization; Macrophages; Mice; Monocyte chemoattractant protein 1; Neovascularization, Physiologic - drug effects; Phenotypes; Pro-angiogenic; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Stimulation; Transforming growth factor-b1; Tumor necrosis factor; Vascular endothelial growth factor; Venom; Wound healing; Wound Healing - drug effects; Disintegrin; Pro-angiogenic; Macrophage polarization; Cytokines; Fibrogenesis
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2021.108224

•Intradermal administration of Jar-C holds a potential therapeutic application in wound healing.•Jararhagin-C inhibits neutrofilic inflammation and pro-inflammatory cytokines production in excisional wounds.•Results highlight the effects of Jar-C promoting M2-macrophage polarization, angiogenesis and collagen deposition.
Jararhagin-C (Jar-C) is a disintegrin-like protein, isolated from the venom of B. jararaca, with affinity for α2β1 integrin and the ability to incite processes such as angiogenesis and collagen deposition in vivo. Thus, we raised the hypothesis that this protein could be used as a therapeutic strategy for stimulating the healing of excisional wounds in mice. Four wounds were made on the back of Swiss mice, treated with daily intradermal injections of PBS (control group) or Jar-C (200 ng). Ten animals from each experimental group were euthanized and the tissue from the wounds and skin around them were collected for further biochemical, histological and molecular analysis. Wounds treated with Jar-C showed a faster closure rate, accompanied by a reduction in neutrophil infiltrate (MPO), pro-inflammatory cytokine levels (TNF, CXCL1 and CCL2) and an accumulation of macrophages in the analyzed tissues. It was also observed a greater expression of genes associated with the phenotype of alternatively activated macrophages (M2). Concomitantly, the administration of Jar-C holds an angiogenic potential, increasing the density of blood vessels and the synthesis of pro-angiogenic cytokines (VEGF and FGF). We also observed an increase in collagen deposition, accompanied by higher levels of the pro-fibrogenic cytokine TGF-β1. Our data suggests Jar-C stimulates wound healing through stimulation of M2-like macrophage, angiogenesis and collagen deposition. Jar-C may be explored as a therapeutic strategy for wound healing, including the treatment of chronic wounds, where processes such as inflammation, angiogenesis and the deposition / remodeling of the matrix constituents are unregulated.