BACKGROUND In 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. METHODS We 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. RESULTS Cold 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. CONCLUSIONS IL-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.

中文翻译：

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移植诱导的缺血-再灌注损伤通过IL-1R8调节来调节供体肾CD11c + F4 / 80 +巨噬细胞的抗原呈递。

背景技术在肾脏移植期间遭受缺血-再灌注损伤的供体肾脏中，共表达F4 / 80和CD11c分子的吞噬细胞通过抗原呈递介导促炎反应并触发移植中的适应性免疫。然而，在受伤后，共表达这些表面标志物的常驻肾巨噬细胞获得了可再生的表型，这对于控制炎症和纤维化至关重要。目前尚无关于移植物诱导的缺血-再灌注损伤对供体来源的常驻肾巨噬细胞充当专业抗原呈递细胞能力的影响的数据。方法我们评估了冷缺血后移植物中CD11c + F4 / 80 +肾巨噬细胞的表型和功能。我们还评估了在先天性肾移植小鼠模型中可逆的缺血再灌注损伤后供体肾巨噬细胞的修饰。为了研究IL-1R8的作用，我们进行了体外和体内研究，比较了来自野生型和IL-R8缺陷型供体的细胞和移植物。结果冷缺血和可逆性缺血再灌注损伤抑制了肾巨噬细胞的抗原呈递，使它们的极化偏向M2表型，并增加了IL-1R8的表面表达，减少了由Toll样受体4介导的活化。缺血性IL-1R8缺陷的供体肾巨噬细胞获得M1表型，有效诱导IFNγ和IL-17反应，未能协调组织修复，导致严重的移植纤维化和异常的体液免疫反应。结论IL-1R8是缺血再灌注损伤后供体肾巨噬细胞功能的关键调节剂，对指导这些细胞的表型和抗原呈递作用至关重要。因此，在肾脏移植后，就调节针对自身抗原和同种抗原的反应而言，它可能代表了一个有趣的途径。