New research has uncovered the function of red blood cells as immune sensors that detect and bind to cell-free DNA present during sepsis.
Red blood cells
Red blood cells (RBCs) comprise the majority of circulating cells within mammals. They are critical for aerobic respiration and also have several non-gas exchanging functions, such as chemokine regulation, complement binding and pathogen immobilisation. While researchers have previously described such functions, RBC immune function still remains a mystery. In circulation, RBCs transit through tissues and come into contact with pathogen and inflammatory mediators. This makes them ideal messengers between distant organs.
During infection, cell-free CpG-containing DNA is elevated. One of the main mechanisms for identifying nucleic acids derived from self and pathogens is via nucleic acid-sensing Toll-like receptors (TLRs). TLRs play a critical role in inflammation. During basal conditions, researchers have demonstrated that RBCs bind and scavenge cell-free (CpG-containing) mitochondrial DNA (cf-mtDNA) away from the lung. Specifically, researchers have discovered that RBCs express intracellular TLR9. However, to date, the role of RBC-dependent CpG binding in the host immune response during inflammatory states is unclear.
RBCs as immune sensors
In a recent study published in Science Translational Medicine, researchers examined the RBCs of around 50 sepsis patients and 100 COVID-19 patients to examine the mechanisms of RBC-DNA binding. The team also wanted to test the hypothesis that RBCs function as DNA sensors and couriers capable of altering the immune response during inflammation.
The researchers found that, during these illnesses, RBCs expressed an increased amount of TLR9 on their surfaces. The results also showed that when RBCs were bound to too many inflammation-causing nucleic acids, they lost their normal structure. This caused the body to no longer recognise them anymore. In turn, this led to their removal from circulation via macrophage erythrophagocytosis. When this occurred, it resulted in the activation of the immune system in otherwise unaffected organs, thus creating inflammation.
Overall, these findings have revealed a previously unappreciated role of RBCs within inflammation. This discovery has opened the door to research on how to block TLR9. Therefore, it could enable researchers to create targeted treatments for autoimmune diseases, infectious diseases and a whole host of inflammatory illnesses that associate with acute anaemia.
Senior author, Nilam Mangalmurti, said:
“Now that we know more about the mechanism of anaemia, it allows us to look at new therapies for treating acute inflammatory anaemia without transfusions, such as blocking TLR9 on the red blood cells. Targeting this TLR9 may also be a way to dampen some of the innate immune activation without blocking this receptor in immune cells, which are very important for the host when fighting a pathogen or injury.”
This discovery also has implications for research into using RBCs in diagnostics. For example, physicians could take blood samples from patients with pneumonia and sequence the nucleic acids that have been soaked up from infection. Here, they could identify the specific pathogen to help better determine what type of antibiotic to prescribe.
The team are now exploring whether this is a valid option for diagnosing infection in critically ill patients and also if this mechanism is universal of anaemia in parasitic infections.
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