High Mobility Group Box 1 Contributes to the Acute Rejection of Liver Allografts by Activating Dendritic Cells.

Yi Chen,Wubing He,Hui Bao,Lihong Chen,Wenmin Zhang

doi:10.3389/fimmu.2021.679398

Abstract

Acute rejection induced by the recognition of donor alloantigens by recipient T cells leads to graft failure in liver transplant recipients. The role of high mobility group box 1 (HMGB1), an inflammatory mediator, in the acute allograft rejection of liver transplants is unknown. Here, rat orthotopic liver transplantation was successfully established to analyze the expression pattern of HMGB1 in liver allografts and its potential role in promoting the maturation of dendritic cells (DCs) to promote T cell proliferation and differentiation. Five and 10 days after transplantation, allografts showed a marked upregulation of HMGB1 expression accompanied by elevated levels of serum transaminase and CD3+ and CD86+ inflammatory cell infiltration. Furthermore, in vitro experiments showed HMGB1 increased the expressions of co-stimulatory molecules (CD80, CD83, and MHC class II) on bone marrow-derived DCs. HMGB1-pulsed DCs induced naive CD4+ T cells to differentiate to Th1 and Th17 subsets secreting IFN-γ and IL-17, respectively. Further in vivo experiments confirmed the administration of glycyrrhizic acid, a natural HMGB1 inhibitor, during donor liver preservation had therapeutic effects by reducing inflammation and hepatocyte damage reflected by a decline in serum transaminase and prolonged allograft survival time. These results suggest the involvement of HMBG1 in acute liver allograft rejection and that it might be a candidate therapeutic target to avoid acute rejection after liver transplantation.

Highlights

Liver transplantation is an optional therapeutic choice for patients with end-stage liver disease [1, 2]
Complicated cross-talk between Dendritic cells (DCs) and alloreactive T cells is involved in acute liver allograft rejection and is regulated by damage-associated molecular pattern molecules (DAMPs) that emerge during ischemia-reperfusion or acute rejection injury [18]
We revealed a vital role for high mobility group box 1 (HMGB1) in acute rejection after liver transplantation indicating it might be a therapeutic target to avoid inflammatory injury caused by acute rejection

Summary

Introduction

Liver transplantation is an optional therapeutic choice for patients with end-stage liver disease [1, 2]. Surgical techniques and immunosuppressive drugs have been greatly improved, acute rejection after liver transplantation remains a major obstacle for long-term graft survival [3, 4]. Dendritic cells (DCs) are professional antigen presenting cells that participate in liver allograft rejection by presenting alloantigens to recipient-derived naïve T cells by direct, indirect, and semi-direct pathways [7, 8]. Donor-derived DCs transferred into the recipient as passengers in the portal tracts and hepatic veins of a liver graft migrate to recipient lymphoid tissues and induce T cell proliferation and differentiation [9]. In the semi-indirect pathway, recipient DCs interact with intact donor MHC molecules on their surface via direct cell–cell interactions or the fusion of exosomes derived from donor DCs, which subsequently trigger T cell activation [11, 12]. Many damage-associated molecular pattern molecules (DAMPs) released from damaged hepatocytes and liver sinusoidal endothelial cells promote cross-talk between DCs and alloreactive T cells, which induce inflammation after liver transplantation [14, 15]

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Conclusion