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Impact of Mitochondrial Permeability on Endothelial Cell Immunogenicity in Transplantation.

ABSTRACT: BACKGROUND:Microvascular endothelial cells (ECs) are central to an allograft's immunogenicity. Cold ischemia and reperfusion injury associated with static cold storage and warm reperfusion activates ECs and increases the immunogenicity of the allograft. After reperfusion, mitochondrial permeability transition pore (mPTP) opening contributes to mitochondrial dysfunction in the allograft, which correlates to alloimmune rejection. Current understanding of this relationship, however, centers on the whole allograft instead of ECs. This study aimed to elucidate the relationship between EC mPTP opening and their immunophenotype. METHODS:Mitochondrial metabolic fitness and glycolysis in ECs were assessed in parallel with metabolic gene microarray postreperfusion. NIM811 was used to inhibit mPTP opening to rescue mitochondrial fitness. The immunogenicity of NIM811-treated ECs was determined via levels of EC's proinflammatory cytokines and allogeneic CD8 T cell cocultures. Finally, EC surface expression of adhesion, costimulatory, coinhibitory, MHC-I molecules, and MHC-I machinery protein levels were characterized. RESULTS:Genes for glycolysis, tricarboxylic acid cycle, fatty acid synthesis, gluconeogenesis were upregulated at 6 hours postreperfusion but either normalized or downregulated at 24 hours postreperfusion. As mitochondrial fitness was reduced, glycolysis increased during the first 6 hours postreperfusion. Endothelial cell treatment with NIM811 during the early postreperfusion period rescued mitochondrial fitness and reduced EC immunogenicity by decreasing CCL2, KC release, and VCAM-1, MHC-I, TAP1 expression. CONCLUSIONS:Static cold storage and warm reperfusion leads to a reduction in mitochondrial fitness in microvascular ECs due to mPTP opening. Further, mPTP opening promotes increased EC immunogenicity that can be prevented by NIM811 treatment.

SUBMITTER: Tran DT

PROVIDER: S-EPMC5962417 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Impact of Mitochondrial Permeability on Endothelial Cell Immunogenicity in Transplantation.

Tran Danh T DT Esckilsen Scott S Mulligan Jennifer J Mehrotra Shikhar S Atkinson Carl C Nadig Satish N SN

Transplantation 20180601 6

<h4>Background</h4>Microvascular endothelial cells (ECs) are central to an allograft's immunogenicity. Cold ischemia and reperfusion injury associated with static cold storage and warm reperfusion activates ECs and increases the immunogenicity of the allograft. After reperfusion, mitochondrial permeability transition pore (mPTP) opening contributes to mitochondrial dysfunction in the allograft, which correlates to alloimmune rejection. Current understanding of this relationship, however, centers ...[more]

PMID: 29538260

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Project description:BackgroundPlatelet (Plt)-derived extracellular vesicles (Plt-EVs) have hemostatic properties similar to Plts. In addition to hemostasis, Plts also function to stabilize the vasculature and maintain endothelial cell (EC) barrier integrity. We hypothesized that Plt-EVs would inhibit vascular EC permeability, similar to fresh Plts. To investigate this hypothesis, we used in vitro and in vivo models of vascular endothelial compromise and bleeding.MethodsIn the vitro model, Plt-EVs were isolated by ultracentrifugation and characterized for Plt markers and particle size distribution. Effects of Plts and Plt-EVs on endothelial barrier function were assessed by transendothelial electrical resistance measurements and histological analysis of endothelial junction proteins. Hemostatic potential of Plt-EVs and Plts was assessed by multiple electrode Plt aggregometry. Using an in vivo model, the effects of Plts and Plt-EVs on vascular permeability and bleeding were assessed in non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice by an established Miles assay of vascular permeability and a tail snip bleeding assay.ResultsIn the in vitro model, Plt-EVs displayed exosomal size distribution and expressed Plt-specific surface markers. Platelets and Plt-EVs decreased EC permeability and restored EC junctions after thrombin challenge. Multiplate aggregometry revealed that Plt-EVs enhanced thrombin receptor-activating peptide-mediated aggregation of whole blood, whereas Plts enhanced thrombin receptor-activating peptide-, arachidonic acid-, collagen-, and adenosine diphosphate-mediated aggregation. In the in vivo model, Plt-EVs are equivalent to Plts in attenuating vascular endothelial growth factor (VEGF)-A-induced vascular permeability and uncontrolled blood loss in a tail snip hemorrhage model.ConclusionOur study is the first to report that Plt-EVs might provide a feasible product for transfusion in trauma patients to attenuate bleeding, inhibit vascular permeability, and mitigate the endotheliopathy of trauma.

Dataset Information

Impact of Mitochondrial Permeability on Endothelial Cell Immunogenicity in Transplantation.

Publications

Impact of Mitochondrial Permeability on Endothelial Cell Immunogenicity in Transplantation.

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