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Background <p>Glucocorticoids(GCs) are widely used to treat erythropoietin-resistant anemias, yet the precise mechanisms underlying their erythropoiesis-promoting effects remain incompletely understood.</p> Methods <p>This study used single-cell RNA sequencing, ATAC-seq, ChIP-seq, RNA-seq,quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry in vivo models (AIHA patients, <i>CD163</i><sup><i>-/-</i></sup> mice, <i>Gypa</i>-eGFP-cremice, <i>Epor</i>-tdtomato-cre mice, and <i>Epor</i>-eGFP-cre rats) and in vitro human erythroblastic island(EBI) formation and EBI enrichment and cytospins, Giemsa&#xa0;and Prussian blue staining, quantification and co-culture systems to delineate CD163<sup>+</sup> macrophages coordinating erythroblastic island formation and iron metabolism.</p> Results <p>GC promote erythropoiesis by regulating CD163-mediated EBI formation and modulating iron metabolism within EBI macrophages, a phenomenon conserved across humans, rats, and mice. We demonstrated that CD163<sup>+</sup>macrophages-but not their CD163<sup>-</sup> counterparts-exhibit heightened iron metabolism in the bone marrow, and that GC-induced erythropoiesis is markedly attenuated in <i>CD163</i>-deficient mice due to disrupted EBI architecture and impaired iron handling. Importantly, GC therapy restores iron metabolism and mitigates inflammatory responses in BM CD163<sup>+</sup>macrophages, likely contributing to improved erythropoiesis in patients with autoimmune hemolytic anemia.</p> Conclusions <p>CD163⁺macrophages support GC-induced erythropoiesis by coordinating erythroblastic island formation and iron metabolism. These findings uncover a previously unrecognized GC-CD163-EBI axis that governs erythropoiesis and highlight the potential of targeting EBI macrophage function as a novel therapeutic strategy for anemia.</p>

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CD163+ macrophages coordinate erythroblastic Island formation and iron metabolism to enable glucocorticoid-induced erythropoiesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月27日

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  • Mengjia Li,
  • Yaomei Wang,
  • Hong Huang,
  • Hao Sun,
  • Mengya Gao,
  • Mingxia Sun,
  • Xudong Li,
  • Zexing Liu,
  • Donghao Liu,
  • Meimei Yan,
  • Zhenghua Huang,
  • Zhen Zhang,
  • Yuhan Hu,
  • Bozheng Wang,
  • Yiwei Zhou,
  • Siyue Li,
  • Yu An,
  • Miao Liu,
  • Yupeng Liu,
  • Fengcai Gao,
  • Fangfang Ge,
  • Wenjuan Fan,
  • Hao Wang,
  • Xing Li,
  • Fang Wang,
  • Guomei Fu,
  • Shiyu Zuo,
  • Binglei Zhang,
  • Jinxin Miao,
  • Chong Wang,
  • Yongping Song,
  • Xiuli An,
  • Weijie Cao,
  • Linping Xu,
  • Wei Li,
  • Zhilei Bian

摘要

Background

Glucocorticoids(GCs) are widely used to treat erythropoietin-resistant anemias, yet the precise mechanisms underlying their erythropoiesis-promoting effects remain incompletely understood.

Methods

This study used single-cell RNA sequencing, ATAC-seq, ChIP-seq, RNA-seq,quantitative PCR (qPCR), enzyme-linked immunosorbent assay (ELISA) and flow cytometry in vivo models (AIHA patients, CD163-/- mice, Gypa-eGFP-cremice, Epor-tdtomato-cre mice, and Epor-eGFP-cre rats) and in vitro human erythroblastic island(EBI) formation and EBI enrichment and cytospins, Giemsa and Prussian blue staining, quantification and co-culture systems to delineate CD163+ macrophages coordinating erythroblastic island formation and iron metabolism.

Results

GC promote erythropoiesis by regulating CD163-mediated EBI formation and modulating iron metabolism within EBI macrophages, a phenomenon conserved across humans, rats, and mice. We demonstrated that CD163+macrophages-but not their CD163- counterparts-exhibit heightened iron metabolism in the bone marrow, and that GC-induced erythropoiesis is markedly attenuated in CD163-deficient mice due to disrupted EBI architecture and impaired iron handling. Importantly, GC therapy restores iron metabolism and mitigates inflammatory responses in BM CD163+macrophages, likely contributing to improved erythropoiesis in patients with autoimmune hemolytic anemia.

Conclusions

CD163⁺macrophages support GC-induced erythropoiesis by coordinating erythroblastic island formation and iron metabolism. These findings uncover a previously unrecognized GC-CD163-EBI axis that governs erythropoiesis and highlight the potential of targeting EBI macrophage function as a novel therapeutic strategy for anemia.