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.

膳食消耗是铁吸收的主要来源，红细胞生成是全身铁需求的主要调节者。除了肠道铁吸收外，巨噬细胞在从衰老红细胞中回收铁方面也发挥着至关重要的作用。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铁调素方面发挥着核心作用。转录调节因子缺氧诱导因子 (HIF)2α 在Epo的调节中发挥核心作用，因此在协调组织串扰以维持全身铁需求方面发挥着至关重要的作用。然而， Hif2α在铁稳态方面对巨噬细胞的精确参与我们的研究表明，删除Hif2α不会破坏铁转运蛋白或基础红细胞生成的表达。与同窝对照小鼠相比，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）方面没有表现出明显的差异。在膳食缺铁和急性红细胞生成需求的条件下观察到这种相似性。值得注意的是，我们观察到缺铁期间十二指肠中铁转运蛋白的表达显着增加，表明铁吸收增加。因此，我们的研究结果表明，骨髓细胞中Hif2α的破坏不会显着影响正常生理条件下的全身铁稳态。然而，它的破坏会引起适应性生理变化，以应对铁需求增加，这可能成为维持红细胞生成需求增加的机制。