Erythropoietin prolongs graft survival in mice by counteracting trained immunity.

Upon activation, macrophages undergo epigenetic and metabolic reprogramming, resulting in stronger responses to subsequent insults (trained immunity), and, in the case of transplant, in accelerated rejection. Erythropoietin (EPO), a kidney-produced erythropoietic hormone, exerts immunomodulatory effects through the ligation of EPO receptor (EPOR) expressed on myeloid cells, but its effects on trained immunity are unknown. C57BL/6 mice receiving BALB/c cardiac allografts and treated with CpG (a toll-like receptor agonist that activates myeloid cells) exhibited accelerated rejection, whereas treatment with EPO-either at the time of CpG injection or afterward-restored prolonged graft survival induced by anti-CD40L monoclonal antibody therapy. Mechanistically, EPO suppressed alloreactive T cell proliferation, enhanced regulatory T cell populations, and reversed CpG-induced inflammatory cytokine production and epigenetic changes in murine macrophages. These effects were absent in mice with myeloid cell-specific deletion of EPOR, underscoring the critical role of EPOR signaling in EPO's protective mechanism. Key results were replicated in human cells. This study demonstrates that EPO counteracts trained immunity in macrophages, promoting immune tolerance and prolonging allograft survival, providing potential therapeutic insights for transplant immunology.