From the Cradle to the Grave: The Role of Macrophages in Erythropoiesis and Erythrophagocytosis

Abstract

Erythropoiesis is a highly regulated process where sequential events ensure the proper differentiation of hematopoietic stem cells into, ultimately, red blood cells (RBCs). Macrophages in the bone marrow play an important role in hematopoiesis by providing signals that induce differentiation and proliferation of the earliest committed erythroid progenitors. Subsequent differentiation toward the erythroblast stage is accompanied by the formation of so-called erythroblastic islands where a central macrophage provides further cues to induce erythroblast differentiation, expansion, and hemoglobinization. Finally, erythroblasts extrude their nuclei that are phagocytosed by macrophages whereas the reticulocytes are released into the circulation. While in circulation, RBCs slowly accumulate damage that is repaired by macrophages of the spleen. Finally, after 120 days of circulation, senescent RBCs are removed from the circulation by splenic and liver macrophages. Macrophages are thus important for RBCs throughout their lifespan. Finally, in a range of diseases, the delicate interplay between macrophages and both developing and mature RBCs is disturbed. Here, we review the current knowledge on the contribution of macrophages to erythropoiesis and erythrophagocytosis in health and disease.

Keywords: RBC clearance; adhesion molecules; erythrophagocytosis; erythropoiesis; macrophages; red blood cells.

Figure 1

Macrophages and erythroblasts form erythroblastic islands through adhesion molecules. Macrophages express several adhesion molecules that facilitate interactions with erythroid precursors of various stages. The intercellular adhesion molecule 4 (ICAM-4) and the α₄β₁ integrin on erythroblasts interact with the α_Vβ₁ integrin and vascular cell adhesion molecule-1 (VCAM-1) on the macrophage. Gradual loss of the α₄β₁ integrin and EMP on the erythroblast facilitates the release of reticulocytes from the erythroblastic island. Persistence of these adhesion molecules on the pyrenocytes is contributing to its phagocytosis by the central macrophage.

Figure 2

“Eat me” and “don’t eat me” signals involved in interaction between macrophages and red blood cell (RBC) regulating clearance. RBCs and macrophages interact with each other through ligand–ligand interactions. Over time, “eat me” signals accumulate on the RBC membrane. Phosphatidylserine (PS) exposed on the RBC membrane can directly bind Stabilin-2, Tim-1, Tim-4, or CD300 on the macrophages and is presumed to give a pro-phagocytic signal. Moreover, bridging molecules such as GAS-6 and lactadherin can facilitate RBC-macrophage interaction by binding PS on RBCs and TAM receptors or α_vβ₃/β₅ integrins on the macrophage. Band 3 clustering and opsonization with Nabs and complement on the RBC enables binding to the macrophage via Fc receptors and CR-1 and thereby facilitates phagocytosis. As a counterbalance, CD47–SIRPα interactions inhibit phagocytosis of RBCs by the macrophage.