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Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury

Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study...

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Autores principales: Namwanje, Maria, Bisunke, Bijay, Rousselle, Thomas V., Lamanilao, Gene G., Sunder, Venkatadri S., Patterson, Elizabeth C., Kuscu, Canan, Kuscu, Cem, Maluf, Daniel, Kiran, Manjari, Mas, Valeria, Eason, James D., Bajwa, Amandeep
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160749/
https://www.ncbi.nlm.nih.gov/pubmed/34065421
http://dx.doi.org/10.3390/ijms22105386
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author Namwanje, Maria
Bisunke, Bijay
Rousselle, Thomas V.
Lamanilao, Gene G.
Sunder, Venkatadri S.
Patterson, Elizabeth C.
Kuscu, Canan
Kuscu, Cem
Maluf, Daniel
Kiran, Manjari
Mas, Valeria
Eason, James D.
Bajwa, Amandeep
author_facet Namwanje, Maria
Bisunke, Bijay
Rousselle, Thomas V.
Lamanilao, Gene G.
Sunder, Venkatadri S.
Patterson, Elizabeth C.
Kuscu, Canan
Kuscu, Cem
Maluf, Daniel
Kiran, Manjari
Mas, Valeria
Eason, James D.
Bajwa, Amandeep
author_sort Namwanje, Maria
collection PubMed
description Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury.
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spelling pubmed-81607492021-05-29 Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury Namwanje, Maria Bisunke, Bijay Rousselle, Thomas V. Lamanilao, Gene G. Sunder, Venkatadri S. Patterson, Elizabeth C. Kuscu, Canan Kuscu, Cem Maluf, Daniel Kiran, Manjari Mas, Valeria Eason, James D. Bajwa, Amandeep Int J Mol Sci Article Dendritic cells (DCs) are unique immune cells that can link innate and adaptive immune responses and Immunometabolism greatly impacts their phenotype. Rapamycin is a macrolide compound that has immunosuppressant functions and is used to prevent graft loss in kidney transplantation. The current study evaluated the therapeutic potential of ex-vivo rapamycin treated DCs to protect kidneys in a mouse model of acute kidney injury (AKI). For the rapamycin single (S) treatment (Rapa-S-DC), Veh-DCs were treated with rapamycin (10 ng/mL) for 1 h before LPS. In contrast, rapamycin multiple (M) treatment (Rapa-M-DC) were exposed to 3 treatments over 7 days. Only multiple ex-vivo rapamycin treatments of DCs induced a persistent reprogramming of mitochondrial metabolism. These DCs had 18-fold more mitochondria, had almost 4-fold higher oxygen consumption rates, and produced more ATP compared to Veh-DCs (Veh treated control DCs). Pathway analysis showed IL10 signaling as a major contributing pathway to the altered immunophenotype after Rapamycin treatment compared to vehicle with significantly lower cytokines Tnfa, Il1b, and Il6, while regulators of mitochondrial content Pgc1a, Tfam, and Ho1 remained elevated. Critically, adoptive transfer of rapamycin-treated DCs to WT recipients 24 h before bilateral kidney ischemia significantly protected the kidneys from injury with a significant 3-fold improvement in kidney function. Last, the infusion of DCs containing higher mitochondria numbers (treated ex-vivo with healthy isolated mitochondria (10 µg/mL) one day before) also partially protected the kidneys from IRI. These studies demonstrate that pre-emptive infusion of ex-vivo reprogrammed DCs that have higher mitochondria content has therapeutic capacity to induce an anti-inflammatory regulatory phenotype to protect kidneys from injury. MDPI 2021-05-20 /pmc/articles/PMC8160749/ /pubmed/34065421 http://dx.doi.org/10.3390/ijms22105386 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Namwanje, Maria
Bisunke, Bijay
Rousselle, Thomas V.
Lamanilao, Gene G.
Sunder, Venkatadri S.
Patterson, Elizabeth C.
Kuscu, Canan
Kuscu, Cem
Maluf, Daniel
Kiran, Manjari
Mas, Valeria
Eason, James D.
Bajwa, Amandeep
Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury
title Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury
title_full Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury
title_fullStr Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury
title_full_unstemmed Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury
title_short Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to Reduce Kidney Ischemic Reperfusion Injury
title_sort rapamycin alternatively modifies mitochondrial dynamics in dendritic cells to reduce kidney ischemic reperfusion injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160749/
https://www.ncbi.nlm.nih.gov/pubmed/34065421
http://dx.doi.org/10.3390/ijms22105386
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