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Mitochondrial-targeted curcumin inhibits T-cell activation via Nrf2 and inhibits graft-versus-host-disease in a mouse
Raghavendra S Patwardhan1, Dievya Gohil2,3, Babita Singh1
1Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.
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.
Insights
Mitochondrial targeted curcumin (MitoC) suppresses T-cell responses by disrupting mitochondrial redox balance, promoting immune suppression for treating graft-versus-host disease. This effect relies on the Nrf2 pathway.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Hyperactive lymphocytes drive pathologies in diseases and transplantation.
- Targeting mitochondrial redox for immune suppression remains underexplored.
Purpose of the Study:
- To investigate mitochondrial redox modulation's impact on T-cell responses.
- To evaluate mitochondrial targeted curcumin (MitoC) as a therapeutic strategy.
- To elucidate the role of Nrf2 in MitoC-mediated immune suppression.
Main Methods:
- MitoC treatment in T cells and Nrf2 knockout mice.
- Flow cytometry, transmission electron microscopy, transcriptomics, and proteomics.
- Assessment of mitochondrial function, T-cell activation, and graft-versus-host disease (GvHD) models.
Main Results:
- MitoC decreased mitochondrial thioredoxin reductase (TrxR) activity, increased mitochondrial reactive oxygen species (mROS), and depleted glutathione.
- MitoC suppressed T-cell activation, promoted T regulatory cell differentiation, and upregulated Nrf2-dependent genes.
- MitoC's effects were abolished in Nrf2 knockout mice, and thiol restoration abrogated T-cell inhibition.
- MitoC ameliorated GvHD symptoms, including reduced lymphoblast formation, inflammatory cytokines, morbidity, and mortality.
Conclusions:
- Disruption of mitochondrial thiols, mediated by MitoC, induces an Nrf2-dependent immune-suppressive state in T cells.
- This mechanism offers a promising therapeutic approach for GvHD and potentially other T-cell mediated pathologies.
- Targeting mitochondrial redox represents a novel strategy for immune modulation.
