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

Background 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. Methods 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. Results 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. Conclusion 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.