Endothelial microparticles delivering microRNA-155 into T lymphocytes are involved in the initiation of acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

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.

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“…This finding, combined with the observation that EMVs bind with CD4+ and CD8+ T cells, may provide another explanation on how EMVs modulate immune response. Other observations support the view that EMVs act as activators of T cells response (159, 160). The number of Th1 cells increased when peripheral blood mononuclear cells were co-incubated with EMVs (159).…”

“…Thus, it may be speculated that EMVs use T-bet to promote Th1 cell differentiation and cytokine synthesis. Subsequent research demonstrated that EMVs deliver miR-155 to T cells (160). Although encapsulated miR-155 does not influence proliferation and apoptosis of T cells, miR-155 inhibition causes suppression of IFN-γ, IL-2, IL-9, and IL-17A release, while increasing the release of other cytokines such as IL-4, IL-6, and IL-10 (160).…”

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“…PBMCs were isolated from mouse peripheral blood samples using the standard Ficoll-Hypaque density gradient centrifugation methods as previously indicated [ 61 , 62 ]. In brief, T lymphocytes were prepared from mouse PBMCs by negative selection with magnetic bead depletion of non-T lymphocytes with the EasySep mouse T lymphocytes isolation kit (Stemcell Technologies, USA) according to the instructions provided by the manufacturer.…”

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“…It has been shown that the dysregulation of miR155 in mouse model drives T H 1 proinflammatory T-cell phenotype (84). In this context, the infusion of EVs loaded with anti-miR155 in preclinical models reduced differentiation toward T H 1, T H 9, and T H 17 cells and skewed differentiation toward T H 2 and Treg cells, thus ameliorating the manifestations of GvHD and increasing mice survival (85).…”