Role of Macrophages in Sickle Cell Disease Erythrophagocytosis and Erythropoiesis

Int J Mol Sci. 2023 Mar 28;24(7):6333. doi: 10.3390/ijms24076333.


Sickle cell disease (SCD) is an inherited blood disorder caused by a β-globin gene point mutation that results in the production of sickle hemoglobin that polymerizes upon deoxygenation, causing the sickling of red blood cells (RBCs). RBC deformation initiates a sequence of events leading to multiple complications, such as hemolytic anemia, vaso-occlusion, chronic inflammation, and tissue damage. Macrophages participate in extravascular hemolysis by removing damaged RBCs, hence preventing the release of free hemoglobin and heme, and triggering inflammation. Upon erythrophagocytosis, macrophages metabolize RBC-derived hemoglobin, activating mechanisms responsible for recycling iron, which is then used for the generation of new RBCs to try to compensate for anemia. In the bone marrow, macrophages can create specialized niches, known as erythroblastic islands (EBIs), which regulate erythropoiesis. Anemia and inflammation present in SCD may trigger mechanisms of stress erythropoiesis, intensifying RBC generation by expanding the number of EBIs in the bone marrow and creating new ones in extramedullary sites. In the current review, we discuss the distinct mechanisms that could induce stress erythropoiesis in SCD, potentially shifting the macrophage phenotype to an inflammatory profile, and changing their supporting role necessary for the proliferation and differentiation of erythroid cells in the disease. The knowledge of the soluble factors, cell surface and intracellular molecules expressed by EBI macrophages that contribute to begin and end the RBC's lifespan, as well as the understanding of their signaling pathways in SCD, may reveal potential targets to control the pathophysiology of the disease.

Keywords: erythroblastic islands; hemolysis; iron; leukocytes; phagocytosis; red blood cells.

Publication types

  • Review

MeSH terms

  • Anemia, Sickle Cell*
  • Erythrocytes
  • Erythropoiesis
  • Humans
  • Inflammation / metabolism
  • Lymphohistiocytosis, Hemophagocytic*
  • Macrophages / metabolism