BackgroundIn donor kidneys subjected to ischemia-reperfusion injury during kidney transplant, phagocytes coexpressing the F4/80 and CD11c molecules mediate proinflammatory responses and trigger adaptive immunity in transplantation through antigen presentation. After injury, however, resident renal macrophages coexpressing these surface markers acquire a proreparative phenotype, which is pivotal in controlling inflammation and fibrosis. No data are currently available regarding the effects of transplant-induced ischemia-reperfusion injury on the ability of donor-derived resident renal macrophages to act as professional antigen-presenting cells.MethodsWe evaluated the phenotype and function of intragraft CD11c+F4/80+ renal macrophages after cold ischemia. We also assessed the modifications of donor renal macrophages after reversible ischemia-reperfusion injury in a mouse model of congeneic renal transplantation. To investigate the role played by IL-1R8, we conducted in vitro and in vivo studies comparing cells and grafts from wild-type and IL-R8–deficient donors.ResultsCold ischemia and reversible ischemia-reperfusion injury dampened antigen presentation by renal macrophages, skewed their polarization toward the M2 phenotype, and increased surface expression of IL-1R8, diminishing activation mediated by toll-like receptor 4. Ischemic IL-1R8–deficient donor renal macrophages acquired an M1 phenotype, effectively induced IFNγ and IL-17 responses, and failed to orchestrate tissue repair, resulting in severe graft fibrosis and aberrant humoral immune responses.ConclusionsIL-1R8 is a key regulator of donor renal macrophage functions after ischemia-reperfusion injury, crucial to guiding the phenotype and antigen-presenting role of these cells. It may therefore represent an intriguing pathway to explore with respect to modulating responses against autoantigens and alloantigens after kidney transplant.
Therapeutic Strategies of Kidney Transplant Ischemia Reperfusion Injury: Insight From Mouse Models