GM-CSF impairs erythropoiesis by disrupting erythroblastic island formation via macrophages

Weijie Cao,Jian Xiang Shi,Meimei Yan,Wenjuan Fan,Fang Wang,Guanghua Wu,Rong Guo,Yinyin Zhang,Chunyan Du,Xiaojing Shi,Zhongxing Jiang,Yingmei Li,Wei Li,Fengcai Gao

doi:10.1186/s12967-021-03214-5

Abstract

Anemia is a significant complication of chronic inflammation and may be related to dysregulated activities among erythroblastic island (EBI) macrophages. GM-CSF was reported to be upregulated and attracted as a therapeutic target in many inflammatory diseases. Among EBIs, we found that the GM-CSF receptor is preferentially and highly expressed among EBI macrophages but not among erythroblasts. GM-CSF treatment significantly decreases human EBI formation in vitro by decreasing the adhesion molecule expression of CD163. RNA-sequence analysis suggests that GM-CSF treatment impairs the supporting function of human EBI macrophages during erythropoiesis. GM-CSF treatment also polarizes human EBI macrophages from M2-like type to M1-like type. In addition, GM-CSF decreases mouse bone marrow (BM) erythroblasts as well as EBI macrophages, leading to a reduction in EBI numbers. In defining the molecular mechanism at work, we found that GM-CSF treatment significantly decreases the adhesion molecule expression of CD163 and Vcam1 in vivo. Importantly, GM-CSF treatment also decreases the phagocytosis rate of EBI macrophages in mouse BM as well as decreases the expression of the engulfment-related molecules Mertk, Axl, and Timd4. In addition, GM-CSF treatment polarizes mouse BM EBI macrophages from M2-like type to M1-like type. Thus, we document that GM-CSF impairs EBI formation in mice and humans. Our findings support that targeting GM-CSF or reprogramming EBI macrophages might be a novel strategy to treat anemia resulting from inflammatory diseases.

Highlights

Granulocyte–macrophage colony-stimulating factor (GM-CSF), a significant myelopoietic growth factor and pro-inflammatory cytokine, has been shown to be upregulated and has attracted increasing interest as a therapeutic target for many inflammatory diseases, including coronavirus disease 2019 (COVID-19; [1,2,3])
GM‐CSF treatment leads to impaired human erythroblastic island (EBI) formation by decreasing adhesion molecule expression of CD163 To begin to study the potential roles of GM-CSF on human EBI formation, we performed human EBI formation assay using “EBI-like” macrophages and late-stage erythroblasts derived from human cord blood CD34+ cells as previously described [17]
To define the mechanisms of the impaired EBI formation, we examined the effects of GM-CSF on adhesion molecules expression of CD163, CD169, EMP, and αV-integrin

Summary

Introduction

Granulocyte–macrophage colony-stimulating factor (GM-CSF), a significant myelopoietic growth factor and pro-inflammatory cytokine, has been shown to be upregulated and has attracted increasing interest as a therapeutic target for many inflammatory diseases, including coronavirus disease 2019 (COVID-19; [1,2,3]). Human GM-CSF stimulates primitive and definitive erythropoiesis in mouse embryos expressing human GM-CSF receptors [8]. GM-CSF levels increased in sickle cell disease (SCD), leading to downregulation of fetal hemoglobin expression [9]. Interleukin-6 (IL-6), interferon-γ (IFN-γ) and GM-CSF were notably unregulated in the mouse model of anemia of inflammation (AI) induced by heat-killed Brucella abortus [10, 11]. Despite these studies, the role of GM-CSF per se in adult human and mouse erythropoiesis remains unclear

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Conclusion