Modulating Donor Mitochondrial Fusion/Fission Delivers Immunoprotective Effects in Cardiac Transplantation

Details

• Alternative Title:
  Am J Transplant
• Personal Author:
  Tran, Danh T. ; Tu, Zhenxiao ; Alawieh, Ali ; Mulligan, Jennifer ; Esckilsen, Scott ; Quinn, Kristen ; Sundararaj, Kamala ; Wallace, Caroline ; Finnegan, Ryan ; Allen, Patterson ; Mehrotra, Shikhar ; Atkinson, Carl ; Nadig, Satish N.
• Description:
  Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC-T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8| T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM-1, MHC-I expression, and increased PD-L1 expression. Co-cultured T cells also displayed decreased memory frequencies and Ki-67 proliferative index. For in vivo significance, we used a novel murine brain-dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain-death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival.
• Subjects:
  Article
• Source:
  Am J Transplant. 22(2):386-401
• Pubmed ID:
  34714588
• Pubmed Central ID:
  PMC8813895
• Document Type:
  Journal Article
• Funding:
  R01 AI142079/AI/NIAID NIH HHSUnited States/ ; S10 OD018113/OD/NIH HHSUnited States/ ; S10 OD018113/CD/ODCDC CDC HHSUnited States/ ; U01 AI132894/AI/NIAID NIH HHSUnited States/ ; T32 GM008716/GM/NIGMS NIH HHSUnited States/ ; T32 HL007260/HL/NHLBI NIH HHSUnited States/ ; R01 AI142079 01A1/National Institute of Allergy and Infectious Diseases/ ; 1UO1AI132894-01/NH/NIH HHSUnited States/
• Volume:
  22
• Issue:
  2
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:5fccc80efb71bbe014a99975a25056c339ec511c2cc8d9ec1342418dca3c1060
• Download URL:
  https://stacks.cdc.gov/view/cdc/114124/cdc_114124_DS1.pdf
• File Type:
  [PDF - 3.17 MB ]