PMID- 34065421
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20220512
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 22
IP  - 10
DP  - 2021 May 20
TI  - Rapamycin Alternatively Modifies Mitochondrial Dynamics in Dendritic Cells to 
      Reduce Kidney Ischemic Reperfusion Injury.
LID - 10.3390/ijms22105386 [doi]
LID - 5386
AB  - 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 
      microg/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.
FAU - Namwanje, Maria
AU  - Namwanje M
AD  - Department of Pediatrics, The University of Tennessee Health Science Center, 
      Memphis, TN 38103, USA.
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, TN 38163, USA.
FAU - Bisunke, Bijay
AU  - Bisunke B
AD  - Department of Genetics, Genomics, and Informatics, College of Medicine, The 
      University of Tennessee Health Science Center, Memphis, TN 38163, USA.
FAU - Rousselle, Thomas V
AU  - Rousselle TV
AD  - Department of Surgery, Surgical Sciences Division, School of Medicine, University 
      of Maryland, Baltimore, MD 21201, USA.
FAU - Lamanilao, Gene G
AU  - Lamanilao GG
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, TN 38163, USA.
FAU - Sunder, Venkatadri S
AU  - Sunder VS
AD  - Department of Systems and Computational Biology, School of Life Sciences, 
      University of Hyderabad, Hyderabad 500046, India.
FAU - Patterson, Elizabeth C
AU  - Patterson EC
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, TN 38163, USA.
FAU - Kuscu, Canan
AU  - Kuscu C
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, TN 38163, USA.
FAU - Kuscu, Cem
AU  - Kuscu C
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, TN 38163, USA.
FAU - Maluf, Daniel
AU  - Maluf D
AD  - Division of Transplant Surgery, University of Maryland Medical Center, School of 
      Medicine, University of Maryland, Baltimore, MD 21201, USA.
FAU - Kiran, Manjari
AU  - Kiran M
AUID- ORCID: 0000-0003-0153-7072
AD  - Department of Systems and Computational Biology, School of Life Sciences, 
      University of Hyderabad, Hyderabad 500046, India.
FAU - Mas, Valeria
AU  - Mas V
AD  - Department of Surgery, Surgical Sciences Division, School of Medicine, University 
      of Maryland, Baltimore, MD 21201, USA.
FAU - Eason, James D
AU  - Eason JD
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, TN 38163, USA.
FAU - Bajwa, Amandeep
AU  - Bajwa A
AUID- ORCID: 0000-0003-0517-8871
AD  - Transplant Research Institute, James D. Eason Transplant Institute, Department of 
      Surgery, College of Medicine, The University of Tennessee Health Science Center, 
      Memphis, TN 38163, USA.
AD  - Department of Genetics, Genomics, and Informatics, College of Medicine, The 
      University of Tennessee Health Science Center, Memphis, TN 38163, USA.
AD  - Department of Microbiology, Immunology, and Biochemistry; College of Medicine, 
      The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
LA  - eng
GR  - R01 DK109581/DK/NIDDK NIH HHS/United States
GR  - R01 DK117183/DK/NIDDK NIH HHS/United States
GR  - R01 DK122682/DK/NIDDK NIH HHS/United States
GR  - R01DK117183/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20210520
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Cytokines)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Acute Kidney Injury/*drug therapy/metabolism
MH  - Adoptive Transfer/methods
MH  - Animals
MH  - Cytokines/metabolism
MH  - Dendritic Cells/*drug effects/metabolism
MH  - HEK293 Cells
MH  - Humans
MH  - Inflammation/metabolism
MH  - Ischemia/*drug therapy/metabolism
MH  - Kidney/drug effects/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mitochondria/*drug effects/metabolism
MH  - Mitochondrial Dynamics/*drug effects
MH  - Reperfusion Injury/*drug therapy/metabolism
MH  - Signal Transduction/drug effects
MH  - Sirolimus/*pharmacology
PMC - PMC8160749
OTO - NOTNLM
OT  - acute kidney injury
OT  - dendritic cell
OT  - ischemic reperfusion injury
OT  - mitochondria
OT  - rapamycin
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/06/03 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/05/20
CRDT- 2021/06/02 01:12
PHST- 2021/04/19 00:00 [received]
PHST- 2021/05/13 00:00 [revised]
PHST- 2021/05/17 00:00 [accepted]
PHST- 2021/06/02 01:12 [entrez]
PHST- 2021/06/03 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2021/05/20 00:00 [pmc-release]
AID - ijms22105386 [pii]
AID - ijms-22-05386 [pii]
AID - 10.3390/ijms22105386 [doi]
PST - epublish
SO  - Int J Mol Sci. 2021 May 20;22(10):5386. doi: 10.3390/ijms22105386.