Abstract
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.
Highlights
Bacterial vaginosis (BV) is one of the most common vaginal infectious diseases among women of reproductive age, and it is difficult to manage clinically [1, 2]
We found that either treatment of Tilapia piscidin 4 (TP4) directly to M1 macrophages or indirectly to vaginal epithelial VK2 cells co-cultured with the M1 macrophages could reduce the inflammatory mediators in the M1 macrophages
To determine if proinflammatory M1 macrophage could be induced by G. vaginalis-secreted factors, a human monocyte cell line (THP-1) and mouse macrophage cell line (RAW264.7) were incubated with 5% or 10% (v/v) G. vaginalis-free culture supernatants (GV sup) for 24 h
Summary
Bacterial vaginosis (BV) is one of the most common vaginal infectious diseases among women of reproductive age, and it is difficult to manage clinically [1, 2]. BV is caused by disturbances in the vaginal microflora; lactobacilli are depleted, allowing the mucosa to become dominated by aerobic and facultative bacteria [3]. Secretion of virulence factors is a major mechanism of G. vaginalis toxicity, as these factors heighten the inflammatory response, decrease the vaginal epithelial integrity, and inhibit tissue repair [6–9]. These effects are largely responsible for BV symptoms and create a more permissive environment for the acquisition and spread of sexually transmitted infections, such as HIV [10]. Antibiotics indiscriminately destroy bacteria, but they may cause adverse effects on the host immune system, such as damage to lymphocyte DNA or reductions in the numbers and functions of macrophages and lymphocytes [12– 14]. It will be beneficial to find new therapeutic options for BV that can improve the risk-benefit ratio for patients by maintaining healthy vaginal microflora and immune function
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