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.

Microglial Corpse Clearance: Lessons From Macrophages

“…The efficient phagocytic removal of apoptotic debris (efferocytosis), mostly carried out by resident macrophages, vastly influences our daily physiology. It is estimated that billions of cells are removed everyday (56): aged erythrocytes and neutrophils in the spleen, liver and bone marrow (57,58), epithelial cells in the mammary gland after the lactation period (59), spermatogenic cells in the testis (60), and the outer segment of light-exposed photoreceptors in the retina (61), among others. In the brain, microglia remove the excess newborn cells produced during embryonic and postnatal development in the cortex, cerebellum and amygdala (62)(63)(64) and in adult neurogenic niches in the hippocampus and subventricular zone (SVZ) (37, 65), as well as deceased cells during aging and neurodegenerative diseases (66).…”

Vascular Drug Delivery Using Carrier Red Blood Cells: Focus on RBC Surface Loading and Pharmacokinetics

“…Moreover, the versatile biomechanical properties of an RBC allow for squeezing through blood vessels of a diameter smaller than itself, creating the opportunity to target vascular endothelia of high-density capillary beds. Lastly, the ability of RBCs to negotiate immune cell clearance in the liver and spleen, until they are senescent, offers a different pathway for presenting antigens to the immune cells in these organs [53,54]. This, coupled with innate immune features of the RBC, allowing for physical adsorption of immune complexes and certain bacteria on the surface and their subsequent transfer to antigen presenting cells (APC) in the spleen, offers opportunities for immunological intervention [55][56][57].…”

Evidence that human and equine erythrocytes could have significant roles in the transport and delivery of amino acids to organs and tissues

“…However, the cells do undergo glycolysis producing lactic acid and they can synthesise glutathione for antioxidant protection (Ataullakhanov et al 1981;Wu et al 2004). Due to the inability to repair or produce proteins, erythrocytes have a limited life span in circulation and, once damaged or aged, are removed from the vascular system and terminated in a process known as eryptosis (Klei et al 2017;Lang et al 2012). In horses, the life span of the erythrocytes is 140-150 days (Carter et al 1974) and in humans, this is averaged at around 115 days (Franco 2012).…”