Red blood cells activate the innate immune system

VSContrary to what you probably learned in school, carrying oxygen is not the only function of red blood cells. In a study published today (October 20) in Science Translational Medicine, The researchers show that these cells, the most abundant in circulation, also alert the immune system to the presence of bacteria, parasites and circulating acellular mitochondrial DNA, which can mean serious illness, such as sepsis or pneumonia. This role of pathogen detection comes at a cost, however: the red blood cells (RBCs) that carry DNA fragments are killed, which probably contributes to the anemia associated with inflammation.

When Nilam Mangalmurti, an intensive care physician and researcher at the University of Pennsylvania, was a pulmonary intensive care researcher in 2005, she became interested in how transfused red blood cells could cause lung damage. This research provided one of the first clues that red blood cells might interact with the immune system, but it was in the context of the transfused cells.

Over the past decade, however, Mangalmurti’s team and other groups have discovered that transfused and circulating red blood cells are not only bags of hemoglobin, but “actually have a multitude of non-exchange functions. gases, “she says,” which “probably have an effect on the host response that we’ve just ignored for all these years. In 2018, for example, her group showed that red blood cells use TLR9 to trap l Cellless mitochondrial DNA, which is present at low levels during normal cell turnover and circulates at high levels during disease or extensive cell death.

Following their publication in 2018, researchers had open questions. First, they wanted to know where TLR9, a receptor involved in the immune response, is found in red blood cells. In the new study, they show that DNA-binding domains of TLR9 can be found on the cell surface of human and murine red blood cells. They also find that, normally, some TLR9 are detectable on a small percentage of healthy red blood cells, but in patients with sepsis or malaria, over 40% of red blood cells had detectable TLR9 on their membranes.

The changes in surface protein levels are unexpected because red blood cells lack a nucleus and therefore cannot alter the expression of their genes and the resulting protein levels based on environmental signals. So, to figure out what they were seeing, the authors treated red blood cells in vitro with DNA. They found that the cells underwent changes in their membranes and took on strange shapes that exposed more TLR9 nucleic acid binding domains, which likely explains the increase seen in patients’ blood samples.

Mangalmurti and his colleagues also used antibody staining to show that these morphological changes mask the CD47 antigen that red blood cells present. CD47 acts as a corporate badge to indicate to the immune system that red blood cells belong to their so-called sense of self. Without it, they can appear foreign. This is because the researchers exposed the red blood cells to DNA or saline and then infused the cells into mice. Within hours, cells exposed to DNA were engulfed by white blood cells in the animals’ spleen, triggering an increase in innate immune signals, such as interferon, in the spleen.

Human red blood cells change shape after treatment with DNA.

LKM LAM ET AL., TRANSLATIONAL MEDICINE SCIENCE, 2021

Removal of red blood cells from the circulation also appears to have a role in anemia, which is common in patients in intensive care units. In people with sepsis and anemia, researchers found more DNA associated with red blood cells than in patients with sepsis who did not have anemia. Circulating mitochondrial DNA has also been shown to be increased during COVID-19 infections. When the authors examined, they found that the amount of mitochondrial DNA stuck to red blood cells correlated with the severity of the disease in COVID-19 patients.

Under normal conditions, red blood cells live their 120 days in circulation, occasionally scavenging DNA and then being eliminated, Mangalmurti explains. “But when there is an acute inflammatory insult, they really take the DNA, lose their self-esteem, break free, and trigger the innate immune response.” In critically ill patients, this can lead to acute inflammatory anemia and oddly shaped red blood cells, which doctors have seen for years without understanding why.

“The role of red blood cells in detecting pathogens is often overlooked,” writes Sizun Jiang, who investigates host-disease interactions at Beth Israel Deaconess Medical Center and Harvard Medical School and has not been involved in the work, written in an email to The scientist. “The authors have done a fantastic job identifying TLR9 on the surface of red blood cells, adding to the growing number of studies challenging the traditional view” that TLR9 is only found inside cells, he adds. he.

“The article indicates that red blood cells can serve as innate immune cells,” not just oxygen carriers, said Rio Sugimura, a biomedical engineer at the University of Hong Kong who was not involved in the study. Sugimura’s group makes red blood cells more easily than T cells in the lab, he says, raising the possibility that red blood cells may be designed to prime immune defenses against pathogens or other attacks.

Another potential application, according to Rafael Polidoro Alves Barbosa, an immunologist at the Indiana School of Medicine who was not involved in the study, is to “develop early biomarkers of systemic inflammation.” If researchers could detect an increase in the population of nucleic acid-positive red blood cells and track its levels over time, he explains, it could signal the need for intervention without the need for more complex diagnostic tests. .

Mangalmurti agrees that the potential for diagnosis and therapy is there. “Just thinking differently about these red blood cells and how those results might apply to different diseases is really fun,” she says. In COVID-19 infections, for example, people infected with the same pathogen have different responses. “Red blood cells can be very different in different patients,” which may help explain the variation in severity of the disease, she explains. “I really hope this will be the start of a lot more people looking at red blood cells and their immune function.”

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