Alberta Transplant Applied Genomics Centre, Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Am J Transplant. 2010 Mar;10(3):490-7. doi: 10.1111/j.1600-6143.2009.02983.x. Epub 2010 Jan 29.
Macrophages display two activation states that are considered mutually exclusive: classical macrophage activation (CMA), inducible by IFNG, and alternative macrophage activation (AMA), inducible by IL4 and IL13. CMA is prominent in allograft rejection and AMA is associated with tissue remodeling after injury. We studied expression of AMA markers in mouse kidney allografts and in kidneys with acute tubular necrosis (ATN). In rejecting allografts, unlike interferon gamma (IFNG) effects and T-cell infiltration that developed rapidly and plateaued by day 7, AMA transcripts (Arg1, Mrc1, Mmp12 and Ear1) rose progressively as tubulitis and parenchymal deterioration developed at days 21 and 42, despite persistent IFNG effects. AMA in allografts was associated with transcripts for AMA inducers IL4, IL13 and inhibin A, but also occurred when hosts lacked IL4/IL13 receptors, suggesting a role for inhibin A. Kidneys with ATN injured by ischemia/reperfusion also had increased expression of AMA markers and inhibin A. Thus kidneys undergoing T-cell-mediated rejection progressively acquire macrophages with alternative activation phenotype despite strong local IFNG effects, independent of IL4 and IL13. Although the mechanisms and causal relationships remain to be determined, high AMA transcript levels in rejecting allografts are strongly associated with and may be a consequence of parenchymal deterioration similar to ATN.
经典的巨噬细胞激活（CMA），可被 IFNG 诱导，和替代的巨噬细胞激活（AMA），可被 IL4 和 IL13 诱导。CMA 在同种异体移植排斥中很明显，而 AMA 与损伤后的组织重塑有关。我们研究了 AMA 标志物在小鼠肾同种异体移植和急性肾小管坏死（ATN）肾脏中的表达。在排斥的同种异体移植中，与干扰素 γ（IFNG）的作用和 T 细胞浸润不同，它们在第 7 天迅速发展并达到平台期，而 AMA 转录物（Arg1、Mrc1、Mmp12 和 Ear1）在第 21 天和第 42 天随着肾小管炎和实质恶化的发展而逐渐升高，尽管 IFNG 作用持续存在。同种异体移植中的 AMA 与 AMA 诱导物 IL4、IL13 和抑制素 A 的转录物有关，但在宿主缺乏 IL4/IL13 受体时也会发生，这表明抑制素 A 发挥作用。缺血/再灌注损伤的 ATN 肾脏也表现出 AMA 标志物和抑制素 A 的表达增加。因此，尽管存在强烈的局部 IFNG 作用，但在 T 细胞介导的排斥中，肾脏逐渐获得具有替代激活表型的巨噬细胞，这与 IL4 和 IL13 无关。尽管机制和因果关系仍有待确定，但排斥的同种异体移植中高 AMA 转录物水平与实质恶化密切相关，可能是其后果，类似于 ATN。
