Knockout of microRNA-155 ameliorates the Th1/Th17 immune response and tissue injury in chronic rejection.
BACKGROUND
MicroRNAs (miRNAs) are integral for maintaining immune homeostasis and self-tolerance. The influence of miRNAs on T-cell differentiation and plasticity are critical in the development of chronic rejection of transplanted hearts. In this study, we sought to determine whether the knockout of miR-155 affects the development of cardiac allograft vasculopathy (CAV) in a murine model.


METHODS
miRNA microarray and quantitative polymerase chain reaction (qPCR) analyses were performed for allograft neointimal lesion samples in chronic rejection. A model of heterotopic murine heart transplantation (bm12 to miR-155+/+or miR-155-/-mice) was then used to analyze allograft survival, histology, mRNA expression and T-cell sub-populations in spleens. The accelerated experiments were performed by intraperitoneal injection of either recombinant interleukin-17A or phosphate-buffered saline (PBS) after heart transplantation. For the competitive transfer experiments, CD4+splenocytes from wild-type (WT) or miR-155-/-mice were mixed and injected into Rag1-/-mice, and cardiac transplantation was performed after 24 hours. The differentiation of T-helper subsets (Th1/Th17/iTreg) was investigated in vitro.


RESULTS
miR-155-/-mice showed resistance to cardiac rejection along with weakened T-cell-mediated inflammation, especially for Th17 cells. Recombinant IL-17A could restore this relieved injury. The competitive experiments implied that miR-155 plays a vital role in the stability of the Th17 phenotype. In vitro, we also demonstrated that miR-155-/-mice exhibit a defect in Th17 differentiation.


CONCLUSIONS
miR-155 regulates Th1/Th17-related inflammation in chronic cardiac rejection and may be a potential therapeutic target to attenuate cardiac allograft rejection. Despite advancements in immunosuppressive therapy, the immunologic mechanisms responsible for allograft rejection remain an important issue for both clinicians and researchers. Allograft rejection is a T-cell-dependent phenomenon and is critically dependent on inflammation mediated by CD4+Th subsets, including Th1, Th2, Th17, Th9 and regulatory T (Treg) cells.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Medicine, Central Hospital of Wuhan, Wuhan, China.
Anchen
A
Zhang
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ke
K
Wang
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cheng
C
Zhou
Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazh'ong University of Science and Technology, Wuhan, China.
Zheng
Z
Gan
Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Dongxia
D
Ma
Department of Cardiovascular Medicine, Central Hospital of Wuhan, Wuhan, China.
Ping
P
Ye
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Yuan
Y
Sun
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jie
J
Wu
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xiaofan
X
Huang
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lingyun
L
Ren
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Peng
P
Deng
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Chuangyan
C
Wu
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Zhang
Z
Yue
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Xiangchao
X
Ding
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Jiuling
J
Chen
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Cardiovascular Medicine, Central Hospital of Wuhan, Wuhan, China; Department of Cardiovascular Surgery, Central Hospital of Wuhan, Wuhan, China. Electronic address: jiahong.xia@mail.hust.edu.cn.
Jiahong
J
Xia
D064591:Allografts; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002908:Chronic Disease; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology; D016027:Heart Transplantation / Q000009:adverse effects* / Q000379:methods; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014181:Transplantation Immunology / Q000235:genetics; D015854:Up-Regulation
D035683:MicroRNAs
CAV; Th17; heart transplantation; miR-155; rejection