Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI; Department of Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI; Department of Medical Scientist Training Program, University of Michigan, Ann Arbor, MI.
Exp Hematol. 2023 Sep-Oct;125-126:25-36.e1. doi: 10.1016/j.exphem.2023.08.001. Epub 2023 Aug 8.
Dietary consumption serves as the primary source of iron uptake, and erythropoiesis acts as a major regulator of systemic iron demand. In addition to intestinal iron absorption, macrophages play a crucial role in recycling iron from senescent red blood cells. The kidneys are responsible for the production of erythropoietin (Epo), which stimulates erythropoiesis, whereas the liver plays a central role in producing the iron-regulatory hormone hepcidin. The transcriptional regulator hypoxia-inducible factor (HIF)2α has a central role in the regulation of Epo, hepcidin, and intestinal iron absorption and therefore plays a crucial role in coordinating the tissue crosstalk to maintain systemic iron demands. However, the precise involvement of Hif2α in macrophages in terms of iron homeostasis remains uncertain. Our study demonstrates that deleting Hif2α in macrophages does not disrupt the expression of iron transporters or basal erythropoiesis. Mice lacking Hif2α in myeloid cells exhibited no discernible differences in hemodynamic parameters, including hemoglobin concentrations and erythrocyte count, when compared with littermate controls. This similarity was observed under conditions of both dietary iron deficiency and acute erythropoietic demand. Notably, we observed a significant increase in the expression of iron transporters in the duodenum during iron deficiency, indicating heightened iron absorption. Therefore, our findings suggest that the disruption of Hif2α in myeloid cells does not significantly impact systemic iron homeostasis under normal physiologic conditions. However, its disruption induces adaptive physiologic changes in response to elevated iron demand, potentially serving as a mechanism to sustain increased erythropoietic demand.
饮食摄入是铁吸收的主要来源，而红细胞生成是调节全身铁需求的主要因素。除了肠道铁吸收外，巨噬细胞在从衰老的红细胞中回收铁方面起着至关重要的作用。肾脏负责产生促红细胞生成素（Epo），刺激红细胞生成，而肝脏在产生铁调节激素hepcidin方面起着核心作用。转录调节因子缺氧诱导因子（HIF）2α在调节 Epo、hepcidin 和肠道铁吸收方面起着核心作用，因此在协调组织串扰以维持全身铁需求方面起着至关重要的作用。然而，Hif2α 在巨噬细胞中对铁平衡的确切参与仍不确定。我们的研究表明，巨噬细胞中 Hif2α 的缺失不会破坏铁转运蛋白或基础红细胞生成的表达。与同窝对照相比，骨髓细胞中缺乏 Hif2α 的小鼠在血流动力学参数（包括血红蛋白浓度和红细胞计数）方面没有明显差异。在饮食缺铁和急性红细胞生成需求的情况下，都观察到了这种相似性。值得注意的是，我们观察到在缺铁期间十二指肠中铁转运蛋白的表达显著增加，表明铁吸收增加。因此，我们的研究结果表明，在正常生理条件下，骨髓细胞中 Hif2α 的缺失不会显著影响全身铁平衡。然而，它的缺失会诱导对升高的铁需求的适应性生理变化，可能作为维持增加的红细胞生成需求的一种机制。
