Myeloid EGR1 contributes to Th17/Treg imbalance during acute liver allograft rejection in a rat model

Abstract

Ischemia-reperfusion injury (IRI) and acute rejection (AR) limit liver transplantation success. Early growth response 1 (EGR1) mediates stress and inflammation, yet its cellular distribution and potential involvement in adaptive alloimmunity during distinct post-transplant stages remain unclear. A rat orthotopic liver transplantation model was used to evaluate graft injury and EGR1 spatiotemporal expression during IRI (6–24 h) and AR (5–10 d). Public scRNA-seq data and virtual knockout analysis were used to assess the cellular distribution and potential regulatory role of Egr1 . EGR1-overexpressing bone marrow-derived dendritic cells (BMDCs) were co-cultured with CD4 + T-cells to assess cytokine secretion, proliferation, and shifted Th17/Treg differentiation. Both syngeneic and allogeneic grafts exhibited early IRI. By days 5–10, allografts developed AR with elevated liver enzymes and Banff scores. EGR1 rose transiently during IRI but re-escalated exclusively in allografts during AR, localizing to portal infiltrates. scRNA-seq showed preferential Egr1 expression in graft myeloid cells, while virtual knockout suggested immune-related regulatory effects. EGR1-associated APC activation and Th17-associated responses were observed in rejecting allografts. EGR1 overexpression in BMDCs promoted pro-inflammatory cytokine secretion, T-cell proliferation, and altered Th17/Treg-associated responses. EGR1 contributes to liver allograft rejection by modulating myeloid APC responses and Th17/Treg-associated T-cell responses, highlighting its potential as a therapeutic target for AR.