Abstract
Endothelial microparticles (EMPs) upregulation has been observed in acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the role of EMPs remains unclear. We found that EMPs derived from TNF-α-stimulated human umbilical vein endothelial cells (EA.hy926) concentrated more microRNA-155 (miR-155) compared with maternal cells. The miR-155 levels in MPs from peripheral blood of aGVHD patients and mice were remarkably elevated and significantly higher than the levels in plasma. Moreover, the rising peak of miR-155 in MPs occurred significantly prior to the peak in T lymphocytes. Additionally, we observed fluorescently-labeled miR-155 in EMPs actively transported into recipient T lymphocytes. Inhibition of miR-155 in EMPs by antagomir-155 did not influence the proliferation and apoptosis of T lymphocytes, but induced defective differentiation toward Th1, Th9 and Th17 cells and skewed differentiation toward Th2 and Treg cells. Furthermore, intravenous injection of miR-155-deficient-EMPs into aGVHD mice significantly attenuated the exacerbation of aGVHD manifestations and abnormal T lymphocytes differentiation induced by high concentration EMPs. Taken together, these data provide a mechanistic framework in which miR-155 delivered by EMPs is involved in aGVHD pathogenesis by activating specific T lymphocytes functions. The results may provide new therapeutic approaches for aGVHD while preserving graft-versus-leukemia (GVL) effect.
Highlights
Acute graft-versus-host disease is still a major contributor to morbidity and mortality following allogeneic hematopoietic stem cell transplantation [1, 2]
For the first time our group explored the intricate interactions between endothelial cells and T lymphocytes through the encapsulation of miR-155 by Endothelial microparticles (EMPs)
Our findings demonstrated that EMPs endogenously released from injured endothelium constituted an effective means of communication between endothelial cells and T lymphocytes and these vesicles were capable of delivering their functional miR-155 into the cytosol of T lymphocytes to promote the development of acute graftversus-host disease (aGVHD)
Summary
Acute graft-versus-host disease (aGVHD) is still a major contributor to morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT) [1, 2]. The detailed pathomechanism underlying the initiation of aGVHD remains poorly understood. Some evidences postulated that endothelial damage played an important role in the initiation of aGVHD [3, 4]. Wagner et al reported that endothelial cells were part of the recipient’s antigen-presenting cell compartment and expressed major histocompatibility complex (MHC)-I and II, costimulatory molecules and cytokines that were indispensable for the activation of T lymphocytes [6]. The activation, cytokine production and expansion of pathogenic alloantigenspecific donor T lymphocytes are hallmarks of aGVHD [1, 7]. The mechanism by which endothelial www.impactjournals.com/oncotarget cells substantially activate and modulate T lymphocytes is unknown
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