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A frog cathelicidin peptide effectively promotes cutaneous wound healing in mice.

ABSTRACT: Although cathelicidins in mammals have been well characterized, little is known about the function of cathelicidin in amphibians. In the present study, a novel 24-residue peptide (cathelicidin-NV, ARGKKECKDDRCRLLMKRGSFSYV) belonging to the cathelicidin family was identified from the skin of the plateau frog Nanorana ventripunctata Cathelicidin-NV showed strong wound healing-promoting activity in a murine model with a full-thickness dermal wound. It directly enhanced the proliferation of keratinocyte cells, resulting in accelerated re-epithelialization of the wound site. Cathelicidin-NV also promoted the proliferation of fibroblasts, the differentiation of fibroblasts to myofibroblasts and collagen production in fibroblasts, which are implicated in wound contraction and repair processes. Furthermore, cathelicidin-NV promoted the release of monocyte chemoattractant protein-1, tumor necrosis factor-?, vascular endothelial growth factor and transforming growth factor-?1 in vivo and in vitro, which are essential in the wound-healing processes such as migration, proliferation and differentiation. The MAPK (ERK, JNK and p38) signaling pathways were involved in the wound healing-promoting effect. Additionally, unlike other cathelicidins, cathelicidin-NV did not have any direct effect on microbes and showed no cytotoxicity and hemolytic activity toward mammalian cells at concentrations up to 200?µg/ml. This current study may facilitate the understanding of the cellular and molecular events that underlie quick wound healing in N. ventripunctata In addition, the combination of these properties makes cathelicidin-NV an excellent candidate for skin wound therapeutics.

SUBMITTER: Wu J

PROVIDER: S-EPMC6134359 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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A frog cathelicidin peptide effectively promotes cutaneous wound healing in mice.

Wu Jing J Yang Jun J Wang Xiaofang X Wei Lin L Mi Kai K Shen Yan Y Liu Tong T Yang Hailong H Mu Lixian L

The Biochemical journal 20180911 17

Although cathelicidins in mammals have been well characterized, little is known about the function of cathelicidin in amphibians. In the present study, a novel 24-residue peptide (cathelicidin-NV, ARGKKECKDDRCRLLMKRGSFSYV) belonging to the cathelicidin family was identified from the skin of the plateau frog <i>Nanorana ventripunctata</i> Cathelicidin-NV showed strong wound healing-promoting activity in a murine model with a full-thickness dermal wound. It directly enhanced the proliferation of k ...[more]

PMID: 30045878

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Project description:Wound healing-promoting peptides exhibit excellent therapeutic potential in regenerative medicine. However, amphibian-derived wound healing-promoting peptides and their mechanism of action remain to be further elucidated. We hereby characterized a wound healing-promoting peptide, Ot-WHP, derived from Chinese concave-eared frog Odorrana tormota. It efficiently promoted wound healing in a mouse model of full-thickness wounds. Ot-WHP significantly increased the number of neutrophils in wounds, and modestly promoted neutrophil phagocytosis and phorbol myristate acetate (PMA)-induced neutrophil extracellular trap formation. Ot-WHP also significantly increased the number of macrophages in wound sites, and directly induced chemokine, cytokine and growth factor production in macrophages by activating mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) signaling pathways. Of note, Ot-WHP did not act as a chemoattractant for neutrophils and macrophages, suggesting its chemotactic activity depends on inducing chemoattractant production in macrophages. Besides, Ot-WHP directly promoted keratinocyte migration by enhancing integrin expression and cell adhesion. In addition, Ot-WHP significantly enhanced the cross-talk between macrophages and keratinocytes/fibroblasts by promoting keratinocyte/fibroblast proliferation, and fibroblast-to-myofibroblast transition despite having no direct effects on keratinocyte/fibroblast proliferation, and fibroblast differentiation. Collectively, Ot-WHP directly elicited the production of regulatory factors in macrophages, consequently initiated and accelerated the inflammatory phase by recruiting neutrophils and macrophages to wounds, and in turn enhanced the cross-talk between macrophages and keratinocytes/fibroblasts, additionally promoted keratinocyte migration, and finally promoted cutaneous wound healing. Our findings provide a promising immunomodulator for acute wound management and new clues for understanding the mechanism of action of amphibian-derived wound healing-promoting peptides.

Project description:BackgroundAmphibian derived pro-healing peptides as molecular probes might provide a promising strategy for development of drug candidates and elucidation of cellular and molecular mechanisms of skin wound healing. A novel skin amphibian peptide, OA-RD17, was tested for modulation of cellular and molecular mechanisms associated with skin wound healing.MethodsCell scratch, cell proliferation, trans-well, and colony formation assays were used to explore the pro-healing ability of peptide OA-RD17 and microRNA-632 (miR-632). Then, the therapeutic effects of OA-RD17 and miR-632 were assessed in mice, diabetic patient ex vivo skin wounds and SD rats. Moreover, hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and immunofluorescence staining were performed to detect skin wound tissue regeneration, inflammatory factors expression, and macrophage polarization. Finally, RNA sequencing, molecular docking, co-localization, dual luciferase reporter, real-time quantitative reverse transcription PCR (RT-qPCR), and Western blotting were used to explore the mechanism of OA-RD17 and miR-632 on facilitating skin wound healing.ResultsThe non-toxic peptide (OA-RD17) promoted macrophage proliferation and migration by activating MAPK and suppressed inflammation by inhibiting NF-κB. In keratinocytes, OA-RD17 inhibited excessive inflammation, and activated MAPK via the Toll-like receptor 4 (TLR4) to promote proliferation and migration, as well as up-regulate the expression of miR-632, which targeted GSK3β to activate Wnt/β-catenin to boost proliferation and migration in a positive feedback manner. Notably, OA-RD17 promoted transition from the inflammatory to proliferative stage, accelerated epidermal and granulation regeneration, and exhibited therapeutic effects on mouse and diabetic patient ex vivo skin wounds. MiR-632 activated Wnt/β-catenin to promote full-thickness skin wound healing in rats.ConclusionsOA-RD17 exhibited promising therapeutic effects on mice (full-thickness, deep second-degree burns), and ex vivo skin wounds in diabetic patients by regulating macrophages proliferation, migration, and polarization (MAPK, NF-κB), and keratinocytes proliferation and migration (TLR4/MAPK/miR-632/Wnt/β-catenin molecular axis). Moreover, miR-632 also activated Wnt/β-catenin to promote full-thickness skin wound healing in rats. Notably, our results indicate that OA-RD17 and miR-632 are promising pro-healing drug candidates.

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A frog cathelicidin peptide effectively promotes cutaneous wound healing in mice.

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A frog cathelicidin peptide effectively promotes cutaneous wound healing in mice.

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