Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Reduced Ceramides Are Associated with Acute Rejection in Liver Transplant Patients and Skin Graft and Hepatocyte Transplant Mice, Reducing Tolerogenic Dendritic Cells

  • Hyun Ju Yoo (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yeogyeong Yi (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Yoorha Kang (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Su Jung Kim (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Young-In Yoon (Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Phuc Huu Tran (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Taewook Kang (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Min Kyung Kim (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jaeseok Han (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Eunyoung Tak (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Chul-Soo Ahn (Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Gi-Won Song (Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Gil-Chun Park (Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Sung-Gyu Lee (Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Jae-Joong Kim (Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Dong-Hwan Jung (Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Shin Hwang (Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Nayoung Kim (Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine)
  • Received : 2023.06.29
  • Accepted : 2023.08.22
  • Published : 2023.11.30
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Abstract

We set up this study to understand the underlying mechanisms of reduced ceramides on immune cells in acute rejection (AR). The concentrations of ceramides and sphingomyelins were measured in the sera from hepatic transplant patients, skin graft mice and hepatocyte transplant mice by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Serum concentrations of C24 ceramide, C24:1 ceramide, C16:0 sphingomyelin, and C18:1 sphingomyelin were lower in liver transplantation (LT) recipients with than without AR. Comparisons with the results of LT patients with infection and cardiac transplant patients with cardiac allograft vasculopathy in humans and in mouse skin graft and hepatocyte transplant models suggested that the reduced C24 and C24:1 ceramides were specifically involved in AR. A ceramide synthase inhibitor, fumonisin B1 exacerbated allogeneic immune responses in vitro and in vivo, and reduced tolerogenic dendritic cells (tDCs), while increased P3-like plasmacytoid DCs (pDCs) in the draining lymph nodes from allogeneic skin graft mice. The results of mixed lymphocyte reactions with ceranib-2, an inhibitor of ceramidase, and C24 ceramide also support that increasing ceramide concentrations could benefit transplant recipients with AR. The results suggest increasing ceramides as novel therapeutic target for AR, where reduced ceramides were associated with the changes in DC subsets, in particular tDCs.

Keywords

Acknowledgement

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT (grant Nos. 2015R1A2A2A04007141 to S.H., 2019R1A2C1009175 to D.-H.J., 2019R1A2C1008880 to J.J.K., and 2012K2A5A5035693 and 2019R1A2C1090895 to N.K.). H.J.Y. was supported by the Basic Science Research Program through the NRF funded by the Ministry of Education (2021R1A6A1A03040260 and 2022R1A2C1007901). The authors thank the Laboratory of Animal Research at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Medical Center for technical support. We are also grateful to Prof. Dr. E. Geissler and Drs. E. Eggenhofer, Jordi Rovira, and Margareta Lantow (University of Regensburg, Regensburg, Germany) for helping us establish mouse models, and to Prof. Jung Bok Lee (Asan Medical Center) for statistical analysis.

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