Leishmania braziliensis resistente ao antimoniato de meglumina imunomodula a resposta de macrófagos murinos M1 e M2 in vitro

Abstract

Leishmania braziliensis is the main etiological agent of cutaneous leishmaniasis (CL), a disease with a high incidence in Brazil, representing a significant public health challenge. Meglumine antimoniate is the standard drug for treating the disease; however, the emergence of resistant strains has hampered its effectiveness. Macrophages act as host cells for Leishmania and play a fundamental role in the immune response against these parasites. The activation of macrophages to the M1 inflammatory profile is crucial for parasite elimination, but there is still little knowledge about how resistant strains of L. braziliensis modulate the plasticity of these cells. Therefore, the objective was to eva-luate the immunomodulation of murine macrophages in in vitro infection by L. brazi-liensis strains resistant (LbR) and susceptible (LbS) to meglumine antimoniate. To this end, murine J774 macrophages were polarized to M1 (with 1μg/ml of LPS) or M2 (with 1μg/ml of IL-4) and then infected with LbR or LbS strains. After 24 and 48h, the fol-lowing were analyzed: parasite load, cytokine production (TNF-α, IL-12, IL-6, IL-4 and IL-10), nitric oxide (NO), urea and arginase activity. The results demonstrated that M1 macrophages infected with LbR presented a significantly higher parasite load compared to those infected with LbS, in both periods evaluated. Regarding inflammatory media-tors, infection with LbR resulted in lower levels of TNF-α, IL-12, and NO in the group of M1 macrophages infected with the LbR strain, compared to M1 macrophages in-fected with the LbS strain. Conversely, in M2 macrophages, infection with LbR induced a significant production of IL-10, IL-4, and IL-6, while LbS did not provoke a relevant response in the production of these cytokines. Arginase and urea modulate the immune response by influencing macrophage polarization and the efficiency of the immune re-sponse to the parasite. These data suggest that the LbR strain has the ability to decrease the production of inflammatory cytokines and NO in M1 macrophages, as well as in-duce the production of regulatory cytokines in M2. This results in a less inflammatory intracellular environment, favoring the survival of the parasite and, consequently, its persistence, which hinders the treatment and cure of the disease. These findings high-light the need for further studies that can deepen the understanding of the resistance mechanisms of these protozoa to traditional therapies, which may contribute to the de-velopment of new, more effective therapeutic strategies.