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Of Macrophages and Red Blood Cells; A Complex Love Story

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Review

Of Macrophages and Red Blood Cells; A Complex Love Story

Djuna Z de Back et al. Front Physiol.

Abstract

Macrophages tightly control the production and clearance of red blood cells (RBC). During steady state hematopoiesis, approximately 10(10) RBC are produced per hour within erythroblastic islands in humans. In these erythroblastic islands, resident bone marrow macrophages provide erythroblasts with interactions that are essential for erythroid development. New evidence suggests that not only under homeostasis but also under stress conditions, macrophages play an important role in promoting erythropoiesis. Once RBC have matured, these cells remain in circulation for about 120 days. At the end of their life span, RBC are cleared by macrophages residing in the spleen and the liver. Current theories about the removal of senescent RBC and the essential role of macrophages will be discussed as well as the role of macrophages in facilitating the removal of damaged cellular content from the RBC. In this review we will provide an overview on the role of macrophages in the regulation of RBC production, maintenance and clearance. In addition, we will discuss the interactions between these two cell types during transfer of immune complexes and pathogens from RBC to macrophages.

Keywords: erythropoiesis; macrophages; phagocytosis; red blood cell; spleen.

Figures

Figure 1
Figure 1
Role of macrophages in erythropoiesis. In the erythroid niche, macrophages not only provide iron for developing erythroblasts but also phagocytose expelled nuclei. Furthermore, the macrophage protein DNaseII is important for breakdown of nuclei that are expelled by erythroblasts.
Figure 2
Figure 2
Direct interactions between the central macrophage and developing erythroblasts. Macrophages express VCAM-1 and integrin αV on their surface facilitating interaction with erythroblasts through integrin α4β 1 and ICAM-4, respectively. Moreover, both erythroid cells and macrophages express Emp on their surface promoting their interactions in the niche. Central macrophage and erythroblast can also interact via the ligand-receptor pair EphB4 (expressed on the surface of erythroblasts) and Ephrin-2, found on macrophages.
Figure 3
Figure 3
Soluble factors important for erythropoiesis. Both central macrophage and erythroblast secrete soluble factors during erythropiesis. These include the negative regulators TNF-α, TGF-β, IL-6, IFN-γ released by the central macrophage, and the positive regulators Gas-6, VEGF-A and PGF released by erythroblasts. TRAIL is a negative regulator secreted by both erythroid cells and macrophages.
Figure 4
Figure 4
Interactions between mature RBC and spleen macrophages. RBC can interact with spleen macrophages via direct receptor ligand pairing or via bridging molecules. Ageing RBC express PS on their surface which can directly bind to Stabilin-2 or Tim-4 on the macrophage or via opsonins such as Gas-6, lactadherin or thrombospondin-1. RBC express CR1 on their surface which can bind C3b osponized particles and further facilitate interaction with spleen macrophages via CR1 and CR3. Nabs can bind Band-3 on the surface of RBC targeting the cell for clearance via Fc receptors on the spleen macrophages. Moreover, RBC express CD47 which binds SIRPα on macrophages.

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