Gardnerella vaginalis is associated with bacterial vaginosis (BV). The virulence factors produced by G. vaginalis are known to stimulate vaginal mucosal immune response, which is largely driven by activated macrophages. While Tilapia piscidin 4 (TP4), an antimicrobial peptide isolated from Nile tilapia, is known to display a broad range of antibacterial functions, it is unclear whether TP4 can affect macrophage polarization in the context of BV. In this study, we used the culture supernatants from G. vaginalis to stimulate differentiation of THP-1 and RAW264.7 cells to an M1 phenotype. The treatment activated the NF-κB/STAT1 signaling pathway, induced reactive nitrogen and oxygen species, and upregulated inflammatory mediators. We then treated the induced M1 macrophages directly with a non-toxic dose of TP4 or co-cultured the M1 macrophages with TP4-treated vaginal epithelial VK2 cells. The results showed that TP4 could not only decrease pro-inflammatory mediators in the M1 macrophages, but it also enriched markers of M2 macrophages. Further, we found that direct treatment with TP4 switched M1 macrophages toward a resolving M2c phenotype via the MAPK/ERK pathway and IL-10-STAT3 signaling. Conversely, tissue repair M2a macrophages were induced by TP4-treated VK2 cells; TP4 upregulated TSG-6 in VK2 cells, which subsequently activated STAT6 and M2a-related gene expression in the macrophages. In conclusion, our results imply that TP4 may be able to attenuate the virulence of G. vaginalis by inducing resolving M2c and tissue repair M2a macrophage polarizations, suggesting a novel strategy for BV therapy.
Wound healing is a highly orchestrated process involving many cell types, such as keratinocytes, fibroblasts and endothelial cells. This study aimed to evaluate the potential application of synthetic peptides derived from tilapia piscidin (TP)2, TP2-5 and TP2-6 in skin wound healing. The treatment of HaCaT keratinocytes with TP2-5 and TP2-6 did not cause cytotoxicity, but did enhance cell proliferation and migration, which could be attributed to the activation of epidermal growth factor receptor signaling. In CCD-966SK fibroblasts, although TP2-5 (31.25 μg/mL) and TP2-6 (125 μg/mL) showed cytotoxic effects, we observed the significant promotion of cell proliferation and migration at low concentrations. In addition, collagen I, collagen III, and keratinocyte growth factor were upregulated by the peptides. We further found that TP2-5 and TP2-6 showed pro-angiogenic properties, including the enhancement of human umbilical vein endothelial cell (HUVEC) migration and the promotion of neovascularization. In a murine model, wounds treated topically with TP2-5 and TP2-6 were reduced by day 2 post-injury and healed significantly faster than untreated wounds. Taken together, these findings demonstrate that both TP2-5 and TP2-6 have multifaceted effects when used as topical agents for accelerating wound healing.
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