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

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.

Neutrophil Extracellular Traps Regulate HMGB1 Translocation and Kupffer Cell M1 Polarization During Acute Liver Transplantation Rejection

“…Following liver transplantation, high-mobility group box-1 (HMGB1), an AR activator after liver transplantation, can activate an immune response (15). Serum HMGB1 levels are significantly elevated in liver transplant patients, and HMGB1 overexpression has been associated with AR development following liver transplantation (16,17).…”

Fast Maturation of Splenic Dendritic Cells Upon TBI Is Associated With FLT3/FLT3L Signaling

“…Not only has HMGB1 been found to contribute to local neuroinflammation upon neurotrauma ( 106 , 107 ), but also it is induced in non-cerebral tissues post-TBI and contributes to the subsequent systemic inflammation following TBI ( 10 ). Notably, HMGB1 is also a major inducer of DC maturation, an effect that appears to be relevant in the context of lung injury (through mTOR signaling) ( 108 ) and in liver injury ( 109 ). Nevertheless, recent evidence has demonstrated the strong involvement of the autonomic system in controlling splenic responses through adrenergic and cholinergic inputs ( 20 , 22 , 45 , 110 , 111 ).…”

The Role of HMGB1 in Rheumatic Diseases

“…(39,125). Targeting HMGB1 therapy has been extensively studied in sepsis, ischemia-perfusion injury, organ transplantation, and tumors (126)(127)(128)(129). In rheumatic diseases, anti-HMGB1 mAb (m2G7) was a relatively wellstudied antibody that played an anti-inflammatory role in collagen-induced arthritis (130).…”