Delaby Constance, Pilard Nathalie, Hetet Gilles, Driss Fathi, Grandchamp Bernard, Beaumont Carole, Canonne-Hergaux François
Inserm U656, Fer et synthèse d'hème, Génétique, Physiologie et Pathologie, Faculté de Médecine Xavier Bichat, 16, rue Henri Huchard, 75018 Paris, France.
Exp Cell Res. 2005 Oct 15;310(1):43-53. doi: 10.1016/j.yexcr.2005.07.002.
Following erythrophagocytosis (EP) of senescent red blood cells (RBCs), heme iron is recycled to the plasma by tissue macrophages. This process is critical for mammalian iron homeostasis but remains elusive. We characterized a cellular model using artificially-aged murine RBCs and murine bone marrow-derived macrophages (BMDMs) and study mRNA and protein expression of HO-1, ferroportin and ferritin after EP. In vitro ageing of RBCs was obtained by raising intracellular calcium concentration. These RBCs exhibit several features of erythrocyte senescence including externalization of phosphatidyl-serine, specific binding and phagocytosis by BMDMs. During the first hours of EP, we observed a rapid increase of HO-1 and ferroportin mRNAs and proteins, whereas ferritin protein expression was progressively induced with no major changes in RNA levels. At later stages after EP, a different pattern of expression was observed with a net decrease of ferroportin, a sustained high level of HO-1, and a strong increase in ferritins. Taken together, these results suggest that after EP, iron is rapidly extracted from heme and exported by ferroportin. Surprisingly, the gene expression profile at late stages after EP, which is indicative of iron storage, is reminiscent of what is observed in inflammation. However, phagocytosis of artificially-aged red blood cells seems to repress the proinflammatory response of macrophages.
在衰老红细胞（RBCs）被吞噬后，血红素铁由组织巨噬细胞再循环至血浆。这一过程对哺乳动物铁稳态至关重要，但仍不清楚。我们使用人工老化的小鼠红细胞和小鼠骨髓来源的巨噬细胞（BMDMs）建立了一个细胞模型，并研究了红细胞吞噬后HO-1、铁转运蛋白和铁蛋白的mRNA和蛋白表达。通过提高细胞内钙浓度实现红细胞的体外老化。这些红细胞表现出红细胞衰老的几个特征，包括磷脂酰丝氨酸外化、被BMDMs特异性结合和吞噬。在红细胞吞噬的最初几个小时，我们观察到HO-1和铁转运蛋白的mRNA和蛋白迅速增加，而铁蛋白蛋白表达逐渐诱导，RNA水平无重大变化。在红细胞吞噬后的后期阶段，观察到不同的表达模式，铁转运蛋白净减少，HO-1持续高水平，铁蛋白强烈增加。综上所述，这些结果表明，红细胞吞噬后，铁迅速从血红素中提取并通过铁转运蛋白输出。令人惊讶的是，红细胞吞噬后期的基因表达谱表明铁储存，这让人联想到炎症中的观察结果。然而，人工老化红细胞的吞噬似乎抑制了巨噬细胞的促炎反应。
