Immune Mechanisms in Inflammatory Anemia

Abstract

Maintaining the correct number of healthy red blood cells (RBCs) is critical for proper oxygenation of tissues throughout the body. Therefore, RBC homeostasis is a tightly controlled balance between RBC production and RBC clearance, through the processes of erythropoiesis and macrophage hemophagocytosis, respectively. However, during the inflammation associated with infectious, autoimmune, or inflammatory diseases this homeostatic process is often dysregulated, leading to acute or chronic anemia. In each disease setting, multiple mechanisms typically contribute to the development of inflammatory anemia, impinging on both sides of the RBC production and RBC clearance equation. These mechanisms include both direct and indirect effects of inflammatory cytokines and innate sensing. Here, we focus on common innate and adaptive immune mechanisms that contribute to inflammatory anemias using examples from several diseases, including hemophagocytic lymphohistiocytosis/macrophage activation syndrome, severe malarial anemia during Plasmodium infection, and systemic lupus erythematosus, among others.

Keywords: anemia; hemophagocyte; hemophagocytic lymphohistiocytosis; inflammation; malaria; sickle cell anemia.

Figure 1

RBC homeostasis and anemia. The proper number of circulating, healthy red blood cells (RBCs) is sustained by a balance of RBC production and clearance. A disruption in either or both processes can lead to anemia. (a) At homeostasis, new RBCs are made in the bone marrow through erythropoiesis and subsequently released into circulation. Simultaneously, old and/or damaged RBCs are cleared from circulation through hemophagocytosis by resident phagocytes in the spleen and liver. (b) Anemia results when one or both sides of this RBC balance is disrupted. Suppressed or aberrant erythropoiesis leads to fewer new, healthy RBCs in circulation. Additionally, RBC destruction can result from infection- or immune-driven hemolysis as well as increased hemophagocytosis by phagocytes in the bone marrow, blood, spleen, and liver. Many immune mechanisms that contribute to anemia have been described and are discussed in this review; including inflammatory cytokines and interferons, autoantibodies to erythropoietin and its receptor, induction of monocyte-derived hemophagocytes, and regulation of positive and negative phagocytic receptors and ligands, among others. Figure adapted from images created with BioRender.com.

Figure 2

Erythropoiesis during inflammatory anemia. (a) Development of megakaryocyte-erythroid progenitors (MEPs) and granulocyte-macrophage progenitors (GMPs) in the bone marrow. Hematopoietic stem cells (HSCs) differentiate into multipotent progenitors (MPPs) and, subsequently, into common myeloid progenitors (CMPs) that make a lineage choice between generating myeloid cells via GMPs or erythrocytes and megakaryocytes via megakaryocyte-erythrocyte progenitors (MEPs). Cross antagonism between the lineage-specifying transcription factors GATA-1 (erythroid lineage) and PU.1 (myeloid lineage) contributes to the relative production of RBCs and myeloid cells. During inflammation, several cytokines, including IFN-α/β, IFN-γ and IL-1β, increase PU.1 expression in CMPs, whereas activation of caspase-1 can cause GATA-1 cleavage, reducing GATA-1-dependent erythropoiesis; both of these activities promote myelopoiesis over erythropoiesis. (b) Interaction between the kidney-derived hormone erythropoietin (EPO) and the EPO receptor (EPOR) on MEPs results in erythroblast differentiation. During terminal erythroblast differentiation erythroblasts acquire iron for hemoglobin synthesis and nuclear condensation occurs. Erythroblasts enucleate and become reticulocytes (immature RBCs), which then exit the bone marrow and differentiate into erythrocytes (mature RBCs) in circulation. During inflammatory anemia, erythropoiesis can be inhibited through the action of many cytokines, including IFN-α, IFN-γ, IL-1β, IL-6, IL-33, and MIF, as well as anti-EPO or anti-EPOR autoantibodies. CD71 is expressed on mouse and human reticulocytes. Ter119 is expressed on mouse reticulocytes and erythrocytes; CD235a is expressed on human reticulocytes and erythrocytes. Figure adapted from images created with BioRender.com.

Figure 3

Signals regulating hemophagocytosis. During many inflammatory, infectious, and autoimmune diseases, increased phagocytic destruction of red blood cells (RBCs) in the spleen, liver, blood, and bone marrow can contribute to anemia. During inflammation, hemophagocytes are licensed by cytokines to phagocytose RBCs (not shown). Prophagocytic signals that promote RBC phagocytosis (left) include the mannose receptor (MR, CD206) binding to high-mannose N-glycans (HMNGs) on RBCs, and Tim-4 binding to surface-exposed phosphatidylserine (PS). Conversely, signals that normally inhibit hemophagocytosis (right) may be absent or decreased during inflammation. For example, disruptions to the SIRPα-CD47 inhibitory axis, such as decreased CD47 expression on RBCs, can lead to hemophagocytosis. Similarly, disruptions of the homotypic interactions of SLAMF3 or SLAMF4 on phagocytes and nucleated erythroblasts can cause hemophagocytosis.