Mitochondrial‐targeted curcumin inhibits T‐cell activation via Nrf2 and inhibits graft‐versus‐host‐disease in a mouse model
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2024
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| author | Raghavendra S. Patwardhan Dievya Gohil Babita Singh Binita K. Kumar Vaitashi Purohit Maikho Thoh Rahul Checker Nilesh Gardi Vikram Gota Vijay Kumar Kutala Sejal Patwardhan Deepak Sharma Santosh K. Sandur |
| author_facet | Raghavendra S. Patwardhan Dievya Gohil Babita Singh Binita K. Kumar Vaitashi Purohit Maikho Thoh Rahul Checker Nilesh Gardi Vikram Gota Vijay Kumar Kutala Sejal Patwardhan Deepak Sharma Santosh K. Sandur Raghavendra S. Patwardhan Dievya Gohil Babita Singh Binita K. Kumar Vaitashi Purohit Maikho Thoh Rahul Checker Nilesh Gardi Vikram Gota Vijay Kumar Kutala Sejal Patwardhan Deepak Sharma Santosh K. Sandur |
| collection | Wiley Open Access |
| contents | Mitochondrial‐targeted curcumin inhibits T‐cell activation via Nrf2 and inhibits graft‐versus‐host‐disease in a mouse model Raghavendra S. Patwardhan Dievya Gohil Babita Singh Binita K. Kumar Vaitashi Purohit Maikho Thoh Rahul Checker Nilesh Gardi Vikram Gota Vijay Kumar Kutala Sejal Patwardhan Deepak Sharma Santosh K. Sandur Phytotherapy Research AbstractAnti‐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. 10.1002/ptr.8126 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/ptr.8126 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_ptr_8126 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Mitochondrial‐targeted curcumin inhibits T‐cell activation via Nrf2 and inhibits graft‐versus‐host‐disease in a mouse model Raghavendra S. Patwardhan Dievya Gohil Babita Singh Binita K. Kumar Vaitashi Purohit Maikho Thoh Rahul Checker Nilesh Gardi Vikram Gota Vijay Kumar Kutala Sejal Patwardhan Deepak Sharma Santosh K. Sandur Phytotherapy Research Mitochondrial‐targeted curcumin inhibits T‐cell activation via Nrf2 and inhibits graft‐versus‐host‐disease in a mouse model Raghavendra S. Patwardhan Dievya Gohil Babita Singh Binita K. Kumar Vaitashi Purohit Maikho Thoh Rahul Checker Nilesh Gardi Vikram Gota Vijay Kumar Kutala Sejal Patwardhan Deepak Sharma Santosh K. Sandur Phytotherapy Research AbstractAnti‐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. 10.1002/ptr.8126 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Mitochondrial‐targeted curcumin inhibits T‐cell activation via Nrf2 and inhibits graft‐versus‐host‐disease in a mouse model |
| topic | Phytotherapy Research |
| url | https://onlinelibrary.wiley.com/doi/10.1002/ptr.8126 |