Leptin enhances the efficacy of glucantime to modulate macrophage polarization toward the M1 phenotype in Leishmania tropica-infected macrophages

Abstract

Background: Macrophages are essential immune cells during Leishmania infection, as their polarization toward M1/M2 phenotypes determines disease outcome. This study aimed to investigate the modulatory effects of leptin, alone and in combination with glucantime, on macrophage polarization in Leishmania tropica infection. Methods: Human THP-1-derived macrophages infected with L. tropica were treated with leptin (5 or 10 ng/ml), glucantime (100 or 200 μg/ml), or their combinations. The cytotoxic effects, parasite survival, reactive oxygen species (ROS), nitric oxide (NO) generation, and expression of M1/M2 acrophage-related parameters were evaluated using standard methods. Results: Both leptin doses significantly increased the expression of M1-associated markers (CD86, iNOS, SOCS3, miR-155) and pro-inflammatory cytokines (TNF-α, IL-12, IFN-γ) while decreasing M2-associated markers (CD206, ARG1, SOCS1, miR-146a) and anti-inflammatory cytokines (IL-4, IL-10, TGF-β). The leptin-glucantime combinations showed synergistic effects, shifting macrophage polarization toward the M1 phenotype more than either treatment alone. In particular, the combination of 10 ng/ml leptin with 100 μg/ml glucantime completely eliminated intracellular amastigotes and showed a superior selectivity index (17.66) compared to mono-treatment (leptin: 7.88; glucantime: 6.87). Conclusions: The findings indicate that leptin enhances the efficacy of glucantime against L. tropica by promoting M1 macrophage polarization. This presents a potential therapeutic approach that may lower conventional drug doses and associated toxicity while preserving or even improving treatment outcomes.