Stress reticulocytes lose transferrin receptors by an extrinsic process involving spleen and macrophages

Abstract

As they mature into erythrocytes during normal erythropoiesis, reticulocytes lose surface transferrin receptors before or concurrently with reticulin. Exosome release accounts for most of the loss of transferrin receptors from reticulocytes. During erythropoietic stress, reticulocytes are released early from hematopoietic tissues and have increased reticulin staining and transferrin receptors. Flow cytometry of dually stained erythrocytes of mice recovering from phlebotomy demonstrated delayed loss of reticulin and transferrin receptors during in vitro maturation compared to in vivo maturation, indicating that an in vivo process extrinsic to the reticulocytes facilitates their maturation. Splenectomy or macrophage depletion by liposomal clodronate inhibited in vivo maturation of reticulocytes and increased the numbers of reticulin-negative, transferrin receptor-positive cells during and after recovery from phlebotomy. This reticulin-negative, transferrin receptor-positive population was rarely found in normal mice. Transmission electron microscopy demonstrated that the reticulin-negative, transferrin receptor-positive cells were elongated and discoid erythrocytes, but they had intracellular and surface structures that appeared to be partially degraded organelles. The results indicate that maturation of circulating stress reticulocytes is enhanced by an extrinsic process that occurs in the spleen and involves macrophage activity. Complete loss of reticulin with incomplete loss of surface transferrin receptors in this process produces a reticulin-negative, transferrin receptor-positive erythrocyte population that has potential utility for detecting prior erythropoietic stresses including bleeding, hemolysis and erythropoietin administration, even after recovery has been completed.

Acute and Chronic Dosing of a High-Affinity Rat/Mouse Chimeric Transferrin Receptor Antibody in Mice

“…Reticulocyte suppression seen with the high-affinity TfRMAb is, therefore, an acute but reversible response. An increase in circulating reticulocytes has been observed following blood loss, hemolysis, or erythropoietin administration [ 24 ], and the increase in reticulocytes seen seven days after the single injection in the current study may be a compensatory stress response associated with reduced reticulocytes seen 24 h after TfRMAb dosing. We also observed a small (3%) but a significant decrease in hemoglobin levels and a trend towards a decrease in RBC in mice treated with TfRMAb seven days after the single injection.…”

Home Sweet Home: Plasmodium vivax-Infected Reticulocytes—The Younger the Better?

“…Recently, CD71 present in younger reticulocytes (CD71+ reticulocytes) has been promoted as the receptor for the P. vivax ligand reticulocyte-binding protein 2b (RBP2b), shedding stronger insight into the strict reticulocyte attraction by P. vivax (Gruszczyk et al, 2018a andGruszczyk et al, 2018b). The suggested dependency on CD71 for invasion has furthermore re-fueled the idea that a great proportion of P. vivax biomass resides in hematopoietic organs, such as the bone marrow (Baird, 2013) (and potentially the spleen, contributing to the final steps of reticulocyte maturation) (Rhodes et al, 2016;Toda et al, 2020). These are environments full of the younger CD71+ reticulocytes and, particularly, the homes of a subset of reticulocytes whose surfaces are extremely enriched in CD71: the CD71 high reticulocytes.…”

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

“…Furthermore, expression of the transferrin receptor is quickly downregulated through exosome release to prevent excessive iron import and toxicity ( 56 ). It is thought that red pulp macrophages (RPMs) of the spleen play an important role in this maturation process, as depletion of macrophages by clodronate treatment inhibits the maturation of reticulocytes in the circulation ( 57 ). How splenic macrophages come into contact with early reticulocytes and promote their maturation into RBCs is still not clear.…”