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⁺CD25^hi 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.

据报道，MicroRNA-155（miR-155）和蛋白质异戊二烯化通过调节 T 淋巴细胞分化参与急性移植物抗宿主病（aGVHD），但其机制仍然难以捉摸。在本研究中，我们发现 aGVHD 小鼠外周血 T 淋巴细胞中 miR-155 和蛋白异戊二烯转移酶的表达显着增加。antagomir-155 抑制 miR-155 可显着降低 aGVHD 小鼠 T 淋巴细胞中异戊二烯转移酶 mRNA 和蛋白的表达。相反，异戊二烯基转移酶抑制剂显着降低了 miR-155 的水平。⁺ CD25 ^hi调节性 T (Treg) 细胞。此外，添加 miR-155 可以逆转异戊二烯基转移酶抑制剂的免疫调节作用和对 aGVHD 的保护作用。异戊二烯化抑制剂和 antagomir-155 的双重治疗显示出对 T 极化和防止 aGVHD 的协同作用。与体内变化一致，抑制 miR-155 的反馈回路和蛋白质异戊二烯化会影响体外 Th17 和 Treg 细胞极化。我们的数据表明，miR-155 和蛋白质异戊二烯化可能构成一个反馈回路，放大 aGVHD 受试者的免疫和炎症反应，它们可能作为 aGVHD 预防和治疗的潜在靶点。