The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity

Abstract

The field of red cell biology is undergoing a quiet revolution. Long assumed to be inert oxygen carriers, RBCs are emerging as important modulators of the innate immune response. Erythrocytes bind and scavenge chemokines, nucleic acids, and pathogens in circulation. Depending on the conditions of the microenvironment, erythrocytes may either promote immune activation or maintain immune quiescence. We examine erythrocyte immune function through a comparative and evolutionary lens, as this framework may offer perspective into newly recognized roles of human RBCs. Next, we review the known immune roles of human RBCs and discuss their activity in the context of sepsis where erythrocyte function may prove important to disease pathogenesis. Given the limited success of immunomodulatory therapies in treating inflammatory diseases, we propose that the immunologic function of RBCs provides an understudied and potentially rich area of research that may yield novel insights into mechanisms of immune regulation.

Figure 1. Comparing the immunologic properties of erythrocytes across vertebrate orders

The erythrocytes of lower vertebrates (i.e., fishes, amphibians, reptiles, and birds) are nucleated in their mature state. Erythrocytes of fish and birds are known to actively undergo transcription and translation, produce and release cytokines, form rosettes to sequester pathogens, and, in the case of trout, phagocytose pathogens. While the activities of erythrocytes in reptiles and amphibians are less well studied, it is likely that they retain many of these characteristics given that they have been maintained across the phylogenetic distance from fish to birds. Despite lacking nuclei and organelles, mammalian (and human) erythrocytes retain the ability to influence innate immunity. All erythrocytes contain hemoglobin, which participates in host defense by generating antimicrobial reactive oxygen species (ROS).

Figure 2. An overview of the binding activities of human erythrocytes

Clockwise from top left. (a) Erythrocytes bind chemokines through the Duffy antigen receptor for chemokines (DARC), thereby modulating neutrophil recruitment and immune activation. (b) Recent studies have shown that erythrocytes are capable of binding and scavenging mitochondrial DNA (mtDNA) via toll-like receptor 9 (TLR9). It is not yet known whether erythroid TLR9 can also scavenge other CpG-rich DNA fragments (e.g., bacterial DNA). (c) Lysed erythrocytes can release heme and hemoglobin into the extracellular environment. In the vicinity of invading microbes, hemoglobin can bind LPS and generate toxic reactive oxygen species (ROS) that function in host defense. However, the release of free heme during states of inflammation can result in excessive immune activation, leading to cellular injury or death. (d) Glycophorin A (GYPA) has been identified as a potential “decoy receptor” on the surface of human erythrocytes, functioning to sequester pathogens and facilitate their removal from circulation.

Figure 3. A systemic model of erythrocyte involvement in critical illness

(a) Under basal conditions, erythrocytes contribute to immune homeostasis by binding and scavenging mitochondrial DNA (mtDNA) via toll-like receptor 9 (TLR9). (b) During states of trauma, extensive cell death leads to increased cell-free mtDNA levels. TLR9-positive erythrocytes scavenge these nucleic acids. Erythrocytes binding mtDNA become crenated (i.e., deformed), which could either expedite their clearance from the circulation or trigger the activation of endothelial cells. Unbound mtDNA may engage immune cells leading to increased inflammation. (c) In sepsis, the circulation is overwhelmed with both bacterial and mitochondrial DNA, as well as free heme (not shown). It remains unknown whether mtDNA-binding capacity of erythrocytes is reduced during sepsis.