The immunological functions of red blood cells

Red blood cells are important mediators of the innate immune system. Depending on the cellular environment, these cells activate the immune system or keep the system in a dormant state. Additionally, red blood cells perform vital immunological functions, including regulation of chemokines, binding of nucleic acids, and clearance of pathogens.

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What are red blood cells?

Red blood cells, or erythrocytes, are the major cell types in circulation, numbering 20 to 30 trillion. The process of producing erythrocytes is called erythropoiesis, which begins in the bone marrow and ends in the circulation. During the process, multipotent hematopoietic stem cells differentiate into erythroid precursor cells, which are then enucleated to form reticulocytes. In the final stage of erythropoiesis, reticulocytes are released into the peripheral circulation, where they transform into erythrocytes. Mature erythrocytes have a lifespan of 120 days, after which they are eliminated by macrophages in the spleen and liver.

The main and well-established function of erythrocytes is to transport oxygen from the lungs to all parts of the body via hemoglobin, an oxygen-carrying pigment in erythrocytes.

What are the immunological functions of erythrocytes?

Erythrocytes have recently been identified as vital modulators of the innate immune system. Despite the absence of a nucleus and the inability to perform transcription and translation, erythrocytes can bind to a wide range of inflammatory molecules, including chemokines, nucleic acids, and pathogens.

In erythrocytes, hemoglobin and heme trigger the production of reactive oxygen species (ROS) to destroy and eliminate hemolytic pathogens. These components of erythrocytes also promote inflammation and autoimmune responses.

Binding to chemokines

Erythrocytes bind to chemokines through Duffy antigen receptors and act as a reservoir of chemokines to prevent chemokine-dependent recruitment of neutrophils. By suppressing neutrophil signaling, erythrocytes help prevent excessive inflammation and tissue damage. Studies have shown that blood lacking erythrocyte surface receptors (Duffy receptors) exhibits elevated levels of plasma chemokines after exposure to lipopolysaccharides.

An alternative theory of the interaction between erythrocytes and chemokines exists. Evidence suggests that erythrocytes bind to chemokines via Duffy receptors in a superficial and reversible manner and then release them into the tissue microenvironment.

These observations indicate that erythrocytes maintain cellular homeostasis by removing chemokines from sites of inflammation or releasing them into tissues in response to reduced plasma levels of chemokines.

Binding to nucleic acids

Erythrocytes can bind nucleic acids, including mitochondrial DNA (mtDNA). Immunostimulatory CpG motifs in mtDNA bind toll-like receptor 9 (TLR9) to initiate pro-inflammatory signaling. Erythrocytes bind and clear mtDNA from circulation via its surface receptor TLR9. Studies in mice have demonstrated that the absence of erythrocyte-mediated mtDNA clearance leads to increased inflammation and lung damage.

Erythrocytes are known to bind bacterial genomic DNA, mtDNA derived from the malaria parasite, and synthetic CpG DNA. During sepsis, plasma CpG DNA levels increase significantly. Binding of erythrocytes to excess CpG DNA via TLR9 leads to morphological alteration of erythrocytes and subsequent erythrophagocytosis via macrophages. Collectively, these processes lead to the development of anemia and the induction of local and systemic inflammation. Studies have shown that increased levels of mtDNA-bound erythrocytes are associated with anemia and disease severity in critically ill patients with coronavirus disease 2019 (COVID-19) with pneumonia.

With respect to other types of nucleic acids, Zika virus genomic RNA has been shown to bind and persist on erythrocytes for several months. However, the clinical consequences of the persistent presence of viral RNA are not fully understood. The recent identification of various TLRs on the surface of erythrocytes, including TLR3, suggests the possibility of erythrocyte binding to other types of nucleic acids via TLRs.

Pathogen binding

Besides cellular components, erythrocytes can bind to invading pathogens, including malaria parasites. Erythrocytes bind to these pathogens via different surface receptors, including Duffy antigen receptors and glycophorin A, B or C.

Glycophorins, especially glycophorin A, act as chaperones to transport pathogens from affected tissues to the spleen to successfully destroy pathogens through macrophages. It is important to note that the binding of pathogens (reovirus, influenza C, E. Coli, etc.) to erythrocytes via glycophorins does not induce infection in erythrocytes, which reinforces the beneficial effects of erythrocytes on the clearance of pathogens.

In contrast, binding of human immunodeficiency virus 1 (HIV-1) to erythrocytes via Duffy receptors leads to persistent viral growth, increasing viral infectivity several-fold.

Nucleated erythrocytes in diseases

Nucleated erythrocytes can be detected in the peripheral blood of 10% to 30% of critically ill patients. The condition is associated with a poor prognosis of the disease. About 50% of patients with nucleated erythrocytes eventually die within 1 to 3 weeks. Although the immunological functions of these cells are largely unknown, there is a hypothesis that nucleated erythrocytes appear in the blood in an attempt to release the maximum number of active immune cells into circulation to counter life-threatening conditions.

The immunological functions of nucleated erythrocytes are well established in non-mammalian vertebrates. In birds, amphibians, and fish, nucleated erythrocytes actively regulate immune responses by producing inflammatory mediators, up-regulating viral response genes, and eliminating pathogens by phagocytosis.

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