10.3389/fimmu.2020.01278.s001
Thomas V. Rousselle
Thomas V.
Rousselle
Canan Kuscu
Canan
Kuscu
Cem Kuscu
Cem
Kuscu
Kailo Schlegel
Kailo
Schlegel
LiPing Huang
LiPing
Huang
Maria Namwanje
Maria
Namwanje
James D. Eason
James D.
Eason
Liza Makowski
Liza
Makowski
Daniel Maluf
Daniel
Maluf
Valeria Mas
Valeria
Mas
Amandeep Bajwa
Amandeep
Bajwa
Image_1_FTY720 Regulates Mitochondria Biogenesis in Dendritic Cells to Prevent Kidney Ischemic Reperfusion Injury.JPEG
Frontiers
2020
dendritic cell
FTY720
mitochondria
sphingosine-1-phosphate receptor
macrophages
metabolism
acute kidney injury
ischemic reperfusion injury
2020-06-24 15:49:47
Figure
https://frontiersin.figshare.com/articles/figure/Image_1_FTY720_Regulates_Mitochondria_Biogenesis_in_Dendritic_Cells_to_Prevent_Kidney_Ischemic_Reperfusion_Injury_JPEG/12555674
<p>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<sup>fl/fl</sup> 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.</p>