RNA Profiling in Human and Murine Transplanted Hearts: Identification and Validation of Therapeutic Targets for Acute Cardiac and Renal Allograft Rejection

L. N. L. Van Aelst, G. Summer, S. Li, S. K. Gupta, W. Heggermont, K. De Vusser, P. Carai, M. Naesens, J. Van Cleemput, F. Van de Werf, J. Vanhaecke, T. Thum, M. Waer, A. -P. Papageorgiou, B. Schroen, S. Heymans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Web of Science)

Abstract

Acute cellular rejection (ACR) is the adverse response of the recipient's immune system against the allogeneic graft. Using human surveillance endomyocardial biopsies (EMBs) manifesting ACR and murine allogeneic grafts, we profiled implicated microRNAs (miRs) and mRNAs. MiR profiling showed that miR-21, -142-3p, -142-5p, -146a, -146b, -155, -222, -223, and -494 increased during ACR in humans and mice, whereas miR-149-5p decreased. mRNA profiling revealed 70 common differentially regulated transcripts, all involved in immune signaling and immune-related diseases. Interestingly, 33 of 70 transcripts function downstream of IL-6 and its transcription factor spleen focus forming virus proviral integration oncogene (SPI1), an established target of miR-155, the most upregulated miR in human EMBs manifesting rejection. In a mouse model of cardiac transplantation, miR-155 absence and pharmacological inhibition attenuated ACR, demonstrating the causal involvement and therapeutic potential of miRs. Finally, we corroborated our miR signature in acute cellular renal allograft rejection, suggesting a nonorgan specific signature of acute rejection. We concluded that miR and mRNA profiling in human and murine ACR revealed the shared significant dysregulation of immune genes. Inflammatory miRs, for example miR-155, and transcripts, in particular those related to the IL-6 pathway, are promising therapeutic targets to prevent acute allograft rejection.
Original languageEnglish
Pages (from-to)99-110
Number of pages12
JournalAmerican Journal of Transplantation
Volume16
Issue number1
DOIs
Publication statusPublished - Jan 2016

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