Welcome to Immunity, Red Blood Cells

In our childhood, we have been taught that our blood cells are divided into immune cells or white blood cells and non-immune cells containing red blood cells (RBCs) and platelets. This blog article shatters that notion and questions if RBCs can join the elite club of immune cells. Previously, Lam and colleagues demonstrated that RBCs have an expression of TLR-9 that binds cell-free mitochondrial CpG DNA inside the cells. They went on to ask whether these cells express TLR-9 on the cell surface as well, to bind potentially harmful cell-free DNA which can act as a foreign substance. Let’s find out what they discovered!

We know erythrocytes or RBCs are an important part of our body- they act as couriers, providing our organs with oxygen and nutritional supplements while on the other hand taking the unnecessary and potentially toxic substances from body organs and helping in removing toxins from the body. Finding out if they have surface TLR-9 expression could forever change our understanding of them.

What are toll-like receptors (TLRs)?

TLRs are protein receptors of our cells that directly bind different pathogen-associated molecular patterns (PAMPs) and initiate a signaling cascade to finally produce antimicrobial peptides. They are commonly present within the cells of the native immune system (e.g. macrophages or neutrophils) that are known for their scavenging properties. CpG motif containing DNA in high levels are hallmarks of infection and can act as PAMPs. In humans, there are ten TLRs and Lam et al. demonstrated that RBCs express TLR-9 that binds to CpG DNA.

How do we know that RBCs express TLR-9 on the surface of their cells?

First, by using antibodies to a larger epitope of the extracellular TLR-9 domain, Lam and collegues detected TLR-9 on the nonpermeabilized human, chimpanzee and murine RBCs. They went further and incubated RBCs with pathogens: the bacteria Legionella pneumophilia and the malaria parasite Plasmodium falciparum), isolated RBCs afterwards and tested them for pathogenic DNA. The presence of pathogenic DNA in RBCs conveyed that RBCs were able to bind those DNA.

Diving into the mechanism, the binding of CpG DNA to TLR-9 on RBCs changes their shape and leads to loss of CD47 signal. CD47 is a marker of self-cells indicating phagocytes not to eat them. So naturally, when CpG DNA binds TLR-9 it will result in the clustering of TLR-9 and CD47, losing the possibility for CD47 to be recognized and will lead to higher erythrophagocytosis of these cells by red-pulp splenic macrophages. These events will in the end lead to anemia and inflammation by higher production of pro-inflammatory cytokines- IFN-γ and IL-6.

Plasma CpG DNA levels are high during the body’s extreme reaction to infection, also known as sepsis. Sepsis is associated with anemia, and enhanced erythrophagocytosis of CpG bound TLR-9 RBCs could be the mechanism behind it. Our researchers reported reduced IL-6 levels after CpG administration in erythrocyte-specific Tlr9-knockout mice compared to wild-type mice, supporting the hypothesis that TLR-9 on RBCs is important for inflammatory response.

The group has also drawn a connection between elevated plasma mitochondrial DNA (mtDNA) in COVID-19 and RBCs. RBC-bound mtDNA was increased in COVID-19 and associated with anaemia and the severity of the disease.

These data suggested that RBCs scavenge DNA by expressing TLR-9 which can lead to enhanced clearance of these RBCs leading to anemia and inflammation. It is fascinating to see such evidences showing RBCs could join the group of innate immune sentinels. If we get season 3 of Cells at work we might see some new roles for our clumsy erythrocyte!

Source: Lam LKM, Murphy S, Kokkinaki D, Venosa A, Sherrill-Mix S, Casu C, Rivella S, Weiner A, Park J, Shin S, Vaughan AE, Hahn BH, Odom John AR, Meyer NJ, Hunter CA, Worthen GS, Mangalmurti NS. DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia. Sci Transl Med. 2021 Oct 20;13(616):eabj1008. doi: 10.1126/scitranslmed.abj1008.

Article author: Ines Poljak. Ines is a MSc graduate from University of Copenhangen who worked on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.

Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.

Check out Antibuddies’ blog post “Welcome to Immunity, Red Blood Cells.”

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