Background:
Localized cutaneous leishmaniasis (LCL) caused by Leishmania braziliensis is characterized by skin ulcers and a strong cellular immune response, despite a low parasite burden in lesions. The mechanisms underlying increased disease severity and the role of programmed cell death in human LCL are not fully understood. Necroptosis, a form of programmed necrosis regulated by the RIPK1–RIPK3–MLKL–PGAM5 axis, is known to influence host immune responses in various diseases, but its specific involvement in human L. braziliensis infection had yet to be investigated.
Abstract:
Methods: An exploratory study was conducted using skin biopsy samples from LCL patients in an endemic area of Brazil to evaluate in situ RNA expression of necroptosis pathway targets. In addition, in vitro assays were performed using THP-1 human macrophages infected with L. braziliensis to examine how the parasite modulates these molecules. mRNA levels were quantified using nCounter technology and RT-qPCR, while protein levels were assessed by western blotting.
Results: Patients with LCL showed a significant reduction in RIPK3 and PGAM5 expression in skin lesions compared to normal skin. In vitro experiments confirmed that L. braziliensis infection directly reduces mRNA and protein levels of RIPK3 and MLKL in human macrophages. Inhibition of RIPK3 and MLKL markedly increased intracellular parasite replication, whereas inhibition of RIPK1 had no significant effect.
Conclusion: Leishmania braziliensis subverts the host necroptotic response by modulating RIPK3 and MLKL expression to promote its own survival and replication within macrophages. These findings suggest that the necroptosis pathway is a critical component of host–parasite interactions and that pharmacological induction or modulation of necroptosis may serve as a potential therapeutic strategy for LCL.
Keywords: RIPK3; MLKL; macrophage; necroptosis; Leishmania braziliensis.
Clique aqui
- Data de Publicação: 28/09/2018
- Autores: Luz NF, Khouri R, Van Weyenbergh J, Zanette DL, Fiuza PP, Noronha A, Barral A, Boaventura VS, Prates DB, Chan FK, Andrade BB, Borges VM.
