Inhibition of the miR-155 and protein prenylation feedback loop alleviated acute graft-versus-host disease through regulating the balance between T helper 17 and Treg cells

• Published in: Transplant immunology Vol. 69; p. 101461
• Main Authors: Wang, Xiaoxiao, Zhang, Ran, Huang, Zhenli, Zang, Sibin, Wu, Qiuling, Xia, Linghui
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2021
• Subjects: Acute Disease; Acute graft-versus-host disease; Allergy and Immunology; Animals; Feedback; Graft vs Host Disease; Mice; Mice, Inbred C57BL; microRNA-155; MicroRNAs - genetics; Polarization; Protein Prenylation; T lymphocyte; T-Lymphocytes, Regulatory; microRNA-155; Acute graft-versus-host disease; Polarization; T lymphocyte; Protein prenylation
• ISSN: 0966-3274; 1878-5492; 1878-5492
• DOI: 10.1016/j.trim.2021.101461

MicroRNA-155(miR-155) and protein prenylation have been reported to participate in acute graft-versus-host disease (aGVHD) through modulating T lymphocyte differentiation, however the mechanism remains elusive. In this study, we found that the expression of miR-155 and protein prenyltransferases in peripheral blood T lymphocytes of aGVHD mice was significantly increased. Suppression of miR-155 by antagomir-155 could remarkably reduce prenyltransferases mRNA and protein expression in T lymphocytes of aGVHD mice. Conversely, prenyltransferase inhibitors significantly reduced the level of miR-155. Inhibition of this feedback loop of miR-155 and protein prenylation in aGVHD mice led to improved survival and lower aGVHD histopathology scores and significantly induced T cell deficient differentiation towards T helper 17 (Th17) cells and titled differentiation towards CD4+CD25hi regulatory T (Treg) cells. Furthermore, the immunoregulatory effects and protection from aGVHD of prenyltransferase inhibitors could be reversed by the addition of miR-155. The dual treatment of prenylation inhibitors and antagomir-155 showed synergistic effects on T polarization and protection from aGVHD. Consistent with the in vivo changes, inhibition of this feedback loop of miR-155 and protein prenylation affected Th17 and Treg cell polarization in vitro. Our data suggest that miR-155 and protein prenylation may constitute a feedback loop that amplifies immune and inflammatory responses in subjects with aGVHD, and they may serve as potential targets for aGVHD prophylaxis and treatment. •MiR-155 and prenyltransferase formed a feedback loop in human T lymphocytes.•Inhibition of the feedback loop between miR-155/protein prenylation affected Th17 and Treg cell polarization in vitro.•MiR-155 levels and protein prenylation were increased and interacted in aGVHD mice.•Suppression of miR-155 or protein prenylation in T lymphocytes alleviated murine aGVHD.•Interventions targeting the miR-155/protein prenylation feedback loop affected Th17 and Treg cell polarization in aGVHD mice.