Cyclosporine A regulates PMN-MDSCs viability and function through MPTP in acute GVHD: Old medication, new target

Xiaoqing Li; Delin Kong; Qiru Yu; Xiaohui Si; Lin Yang; Xiangjun Zeng; Yixue Li; Jimin Shi; Pengxu Qian; He Huang; Yu Lin

doi:10.1016/j.jtct.2022.04.010

Cyclosporine A regulates PMN-MDSCs viability and function through MPTP in acute GVHD: Old medication, new target

Transplant Cell Ther. 2022 Jul;28(7):411.e1-411.e9. doi: 10.1016/j.jtct.2022.04.010. Epub 2022 Apr 14.

Authors

Xiaoqing Li¹, Delin Kong¹, Qiru Yu¹, Xiaohui Si¹, Lin Yang², Xiangjun Zeng¹, Yixue Li¹, Jimin Shi¹, Pengxu Qian², He Huang³, Yu Lin⁴

Affiliations

¹ Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.
² Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.
³ Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China. Electronic address: huanghe@zju.edu.cn.
⁴ Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China. Electronic address: linyu517@zju.edu.cn.

PMID: 35430420
DOI: 10.1016/j.jtct.2022.04.010

Abstract

Myeloid-derived suppressor cells (MDSCs), a population of myeloid lineage cells with immunosuppressive capacity, can mitigate acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We previously found that the immunosuppressive function of polymorphonuclear population (PMN-MDSCs) was impaired in aGVHD milieu. The aim of this study was to explore the intrinsic mechanism regulating the fate and function of donor-derived PMN-MDSCs during allo-HSCT. We firstly found that mitochondrial permeability transition pore (MPTP) opened in the PMN-MDSCs in response to the intense inflammatory environment of aGVHD, which induced mitochondrial damage, oxidative stress, and apoptosis of PMN-MDSCs. Inhibiting MPTP opening by a traditional immunosuppressant, cyclosporine A (CsA), could restore the immunosuppressive function and viability of PMN-MDSCs in vitro and in vivo, which reveals a new mechanism of CsA application.

Keywords: Allo-HSCT; Cell death; MDSCs; MPTP; Mitochondria; aGVHD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cyclosporine / pharmacology
Graft vs Host Disease* / drug therapy
Humans
Immunosuppressive Agents / pharmacology
Mitochondrial Permeability Transition Pore
Myeloid-Derived Suppressor Cells*

Substances

Cyclosporine
Immunosuppressive Agents
Mitochondrial Permeability Transition Pore