PMID- 32670281 OWN - NLM STAT- MEDLINE DCOM- 20210402 LR - 20210402 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury. PG - 1278 LID - 10.3389/fimmu.2020.01278 [doi] LID - 1278 AB - Dendritic cells (DCs) are central in regulating immune responses of kidney ischemia-reperfusion injury (IRI), and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5), and protection from kidney IRI occurs in mice treated with S1PR agonist, FTY720 (FTY). We tested if ex vivo propagation of DCs with FTY could be used as cellular therapy to limit the off-target effects associated with systemic FTY administration in kidney IRI. DCs have the ability of regulate innate and adaptive responses and we posited that treatment of DC with FTY may underlie improvements in kidney IRI. Herein, it was observed that treatment of bone marrow derived dendritic cells (BMDCs) with FTY induced mitochondrial biogenesis, FTY-treated BMDCs (FTY-DCs) showed significantly higher oxygen consumption rate and ATP production compared to vehicle treated BMDCs (Veh-DCs). Adoptive transfer of FTY-DCs to mice 24 h before or 4 h after IRI significantly protected the kidneys from injury compared to mice treated with Veh-DCs. Additionally, allogeneic adoptive transfer of C57BL/6J FTY-DCs into BALB/c mice equally protected the kidneys from IRI. FTY-DCs propagated from S1pr1-deficient DCs derived from CD11cCreS1pr1(fl/fl) mice as well as blunting mitochondrial oxidation in wildtype (WT) FTY-DCs prior to transfer abrogated the protection observed by FTY-DCs. We queried if DC mitochondrial content alters kidney responses after IRI, a novel but little studied phenomenon shown to be integral to regulation of the immune response. Transfer of mitochondria rich FTY-DCs protects kidneys from IRI as transferred FTY-DCs donated their mitochondria to recipient splenocytes (i.e., macrophages) and prior splenectomy abrogated this protection. Adoptive transfer of FTY-DCs either prior to or after ischemic injury protects kidneys from IRI demonstrating a potent role for donor DC-mitochondria in FTY's efficacy. This is the first evidence, to our knowledge, that DCs have the potential to protect against kidney injury by donating mitochondria to splenic macrophages to alter their bioenergetics thus making them anti-inflammatory. In conclusion, the results support that ex vivo FTY720-induction of the regulatory DC phenotype could have therapeutic relevance that can be preventively infused to reduce acute kidney injury. CI - Copyright (c) 2020 Rousselle, Kuscu, Kuscu, Schlegel, Huang, Namwanje, Eason, Makowski, Maluf, Mas and Bajwa. FAU - Rousselle, Thomas V AU - Rousselle TV AD - Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United States. FAU - Kuscu, Canan AU - Kuscu C AD - Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United States. FAU - Kuscu, Cem AU - Kuscu C AD - Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United States. FAU - Schlegel, Kailo AU - Schlegel K AD - Division of Nephrology and the Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United States. FAU - Huang, LiPing AU - Huang L AD - Division of Nephrology and the Center for Immunity, Inflammation and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA, United States. FAU - Namwanje, Maria AU - Namwanje M AD - Department of Pediatrics and Genetics, University of Tennessee Health Science Center, Memphis, TN, United States. FAU - Eason, James D AU - Eason JD AD - Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United States. FAU - Makowski, Liza AU - Makowski L AD - Department of Medicine - Division of Hematology and Oncology, College of Medicine, Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Sciences Center, Memphis, TN, United States. FAU - Maluf, Daniel AU - Maluf D AD - Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United States. FAU - Mas, Valeria AU - Mas V AD - Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United States. FAU - Bajwa, Amandeep AU - Bajwa A AD - Transplant Research Institute, James D. Eason Transplant Institute, Department of Surgery, School of Medicine, University of Tennessee Health Sciences Center, Memphis, TN, United States. LA - eng GR - R01 DK117183/DK/NIDDK NIH HHS/United States GR - R01 DK080074/DK/NIDDK NIH HHS/United States GR - R03 DK107941/DK/NIDDK NIH HHS/United States GR - R01 DK109581/DK/NIDDK NIH HHS/United States GR - K01 DK091444/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200623 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - G926EC510T (Fingolimod Hydrochloride) SB - IM MH - Acute Kidney Injury/etiology/*prevention & control MH - Adoptive Transfer MH - Animals MH - Dendritic Cells/*drug effects/*transplantation MH - Fingolimod Hydrochloride/*pharmacology MH - Macrophages/*metabolism MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred C57BL MH - Mitochondria/*drug effects/metabolism MH - Organelle Biogenesis MH - Reperfusion Injury/complications PMC - PMC7328774 OTO - NOTNLM OT - FTY720 OT - acute kidney injury OT - dendritic cell OT - ischemic reperfusion injury OT - macrophages OT - metabolism OT - mitochondria OT - sphingosine-1-phosphate receptor EDAT- 2020/07/17 06:00 MHDA- 2021/04/07 06:00 PMCR- 2020/01/01 CRDT- 2020/07/17 06:00 PHST- 2019/12/24 00:00 [received] PHST- 2020/05/20 00:00 [accepted] PHST- 2020/07/17 06:00 [entrez] PHST- 2020/07/17 06:00 [pubmed] PHST- 2021/04/07 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.01278 [doi] PST - epublish SO - Front Immunol. 2020 Jun 23;11:1278. doi: 10.3389/fimmu.2020.01278. eCollection 2020.