Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
The Academy of Medical Science, College of Medical, Zhengzhou University, Zhengzhou, 450052, Henan, China.
J Transl Med. 2022 Jan 3;20(1):11. doi: 10.1186/s12967-021-03214-5.
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.
贫血是慢性炎症的一种严重并发症，可能与红细胞生成岛（EBI）巨噬细胞中失调的活动有关。GM-CSF 已被报道在许多炎症性疾病中上调，并作为治疗靶点被吸引。在 EBI 中，我们发现 GM-CSF 受体在 EBI 巨噬细胞中优先且高度表达，而不是在红细胞中。GM-CSF 治疗通过降低 CD163 的粘附分子表达，显著减少体外人 EBI 的形成。RNA 序列分析表明，GM-CSF 治疗在红细胞生成过程中损害了人 EBI 巨噬细胞的支持功能。GM-CSF 治疗还将人 EBI 巨噬细胞从 M2 样类型极化到 M1 样类型。此外，GM-CSF 减少小鼠骨髓（BM）中的红细胞和 EBI 巨噬细胞，导致 EBI 数量减少。在确定起作用的分子机制时，我们发现 GM-CSF 治疗显著降低了体内 CD163 和 Vcam1 的粘附分子表达。重要的是，GM-CSF 治疗还降低了小鼠 BM 中 EBI 巨噬细胞的吞噬率，并降低了吞噬相关分子 Mertk、Axl 和 Timd4 的表达。此外，GM-CSF 治疗将小鼠 BM EBI 巨噬细胞从 M2 样类型极化到 M1 样类型。因此，我们证明 GM-CSF 会损害小鼠和人类的 EBI 形成。我们的发现支持靶向 GM-CSF 或重新编程 EBI 巨噬细胞可能是治疗炎症性疾病引起的贫血的一种新策略。
