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

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