Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA.
Laboratory of Immunochemistry, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.
Cell. 2014 Mar 13;156(6):1223-1234. doi: 10.1016/j.cell.2014.01.069.
Splenic red pulp macrophages (RPM) degrade senescent erythrocytes and recycle heme-associated iron. The transcription factor SPI-C is selectively expressed by RPM and is required for their development, but the physiologic stimulus inducing Spic is unknown. Here, we report that Spic also regulated the development of F4/80(+)VCAM1(+) bone marrow macrophages (BMM) and that Spic expression in BMM and RPM development was induced by heme, a metabolite of erythrocyte degradation. Pathologic hemolysis induced loss of RPM and BMM due to excess heme but induced Spic in monocytes to generate new RPM and BMM. Spic expression in monocytes was constitutively inhibited by the transcriptional repressor BACH1. Heme induced proteasome-dependent BACH1 degradation and rapid Spic derepression. Furthermore, cysteine-proline dipeptide motifs in BACH1 that mediate heme-dependent degradation were necessary for Spic induction by heme. These findings are the first example of metabolite-driven differentiation of a tissue-resident macrophage subset and provide new insights into iron homeostasis.
脾脏红髓巨噬细胞（RPM）降解衰老的红细胞并回收血红素相关铁。转录因子 SPI-C 特异性表达于 RPM，是其发育所必需的，但诱导 Spi 的生理刺激尚不清楚。在这里，我们报告 Spi 还调节 F4/80（+）VCAM1（+）骨髓巨噬细胞（BMM）的发育，并且血红素诱导 Spic 在 BMM 和 RPM 发育中的表达，血红素是红细胞降解的代谢物。病理性溶血由于血红素过多而导致 RPM 和 BMM 的丧失，但诱导单核细胞中的 Spic 生成新的 RPM 和 BMM。转录抑制因子 BACH1 持续抑制单核细胞中的 Spic 表达。血红素诱导蛋白酶体依赖性 BACH1 降解和 Spic 快速去抑制。此外，BACH1 中介导血红素依赖性降解的半胱氨酸-脯氨酸二肽基序对于血红素诱导 Spic 是必需的。这些发现是代谢物驱动组织驻留巨噬细胞亚群分化的首例，为铁稳态提供了新的见解。
