Mitochondrial-targeted curcumin inhibits T-cell activation via Nrf2 and inhibits graft-versus-host-disease in a mouse model.
Phytother Res
; 38(3): 1555-1573, 2024 Mar.
Article
en En
| MEDLINE
| ID: mdl-38281735
ABSTRACT
Anti-inflammatory and immune suppressive agents are required to moderate hyper-activation of lymphocytes under disease conditions or organ transplantation. However, selective disruption of mitochondrial redox has not been evaluated as a therapeutic strategy for suppression of T-cell-mediated pathologies. Using mitochondrial targeted curcumin (MitoC), we studied the effect of mitochondrial redox modulation on T-cell responses by flow cytometry, transmission electron microscopy, transcriptomics, and proteomics, and the role of Nrf2 was studied using Nrf2- /- mice. MitoC decreased mitochondrial TrxR activity, enhanced mitochondrial ROS (mROS) production, depleted mitochondrial glutathione, and suppressed activation-induced increase in mitochondrial biomass. This led to suppression of T-cell responses and metabolic reprogramming towards Treg differentiation. MitoC induced nuclear translocation and DNA binding of Nrf2, leading to upregulation of Nrf2-dependent genes and proteins. MitoC-mediated changes in mitochondrial redox and modulation of T-cell responses are abolished in Nrf2- /- mice. Restoration of mitochondrial thiols abrogated inhibition of T-cell responses. MitoC suppressed alloantigen-induced lymphoblast formation, inflammatory cytokines, morbidity, and mortality in acute graft-versus-host disease mice. Disruption of mitochondrial thiols but not mROS increase inculcates an Nrf2-dependent immune-suppressive disposition in T cells for the propitious treatment of graft-versus-host disease.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Curcumina
/
Enfermedad Injerto contra Huésped
Límite:
Animals
Idioma:
En
Revista:
Phytother Res
Asunto de la revista:
TERAPIAS COMPLEMENTARES
Año:
2024
Tipo del documento:
Article
País de afiliación:
India