Sub-Journal of "Science": Red blood cells also control immunity!

It was the first time I learned from textbooks that "mature red blood cells lose their nuclei and organelles, and are mainly responsible for transporting oxygen in the body.
" The red blood cells in the heart of Singularity Cake are like this: cute love, no brain cell nucleus.
Later I learned that the human body The 30 trillion red blood cells are more than just oxygen transporters
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Due to the large number and the ability to travel almost every corner of the human body, red blood cells also serve as a "sentinel", promptly detecting pathogens or damage in the body, and issuing warnings to the immune system [1-3]
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The red blood cells in the heart of Singularity Cake have become like this again: I will show you the white blood cell brothers! Recently, another research team discovered that the cell surface of red blood cells can also adhere to DNA molecules, thereby participating in innate immunity [3,4]! Nilam S.
Mangalmurti and his team from the Perelman School of Medicine at the University of Pennsylvania found that the appearance of a CpG-rich DNA molecule in the human body is associated with inflammation, and the Toll-like receptor 9 (TLR9) expressed by red blood cells can Recognize and bind this DNA, which is then recognized and cleared by macrophages, alleviating tissue damage caused by inflammation [4]
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This not only proves that red blood cells are a vital member of innate immunity, but also explains why anemia is always accompanied by systemic inflammation
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The article was published in the journal Science Translational Medicine
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Screenshot of the paper's homepage.
For CpG DNA, you may not be familiar with it.
It is a DNA molecule rich in 5'-C-phosphate-G-3'
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The exact shape of the molecule is not important here.
In short, pathogens that invade the human body will carry this DNA, and CpG DNA will be released when the cells in the body are damaged [5-8]
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Studies have found that the increase in the level of free CpG DNA in the body is significantly related to the occurrence of malignant tumors, autoimmune diseases, and sepsis [5-8]
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So, how does the human body deal with these signaling DNA molecules? In fact, in 2018, Mangalmurti's team proved that red blood cells are necessary to clear CpG DNA and reduce lung tissue damage
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They found that when inflammation occurs in the human body, red blood cells can recognize and bind free CpG DNA by expressing TLR9, and then.
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, reduce tissue damage [3]
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This group of ellipsis is really not a lazy singularity cake
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Although Mangalmurti and his team discovered that red blood cells can capture CpG DNA, what happened after that? How is CpG DNA stuck to red blood cells removed? This left a deep doubt for Mangalmurti's team
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In 2018, Mangalmurti and his team made this discovery[3] and now, Mangalmurti and his team have added this important link! First they made a small addition
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In previous experiments, they only detected TLR9 in red blood cells
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This time, they successfully detected the surface of red blood cells in mice and humans, and found that the expression of TLR9 in mammals is very conservative, and the DNA binding domain is outside the cell
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 After confirming that red blood cells rely on the recognition and binding of TLR9 and CpG DNA on the cell surface, researchers began to think: What effect will the morphology of red blood cells be affected by an additional attachment on the body? They found that the binding of a small amount of CpG DNA is still a small case for red blood cells and has no effect
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However, when the number of CpG DNA bound to the cell surface increases, red blood cells will still be overwhelmed, the distribution of cytoskeleton proteins will change significantly, and the whole cell will shrink, but the integrity of the cell membrane is still maintained
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 This is a serious red blood cell-it will shrink when combined with a large amount of CpG DNA [2] Not only that, once the CpG DNA is carried, the red blood cell will lose its life
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 After being produced in the bone marrow, red blood cells will circulate in the blood for approximately 120 days
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During their lifetime, red blood cells pass through the liver and spleen many times, where they encounter macrophages, and macrophages usually engulf aging and damaged red blood cells [9]
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Normal red blood cells can safely pass in front of macrophages because CD47 is expressed on the cell surface, which is a "don't eat me" signal
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As soon as the macrophages see the red blood cells holding CD47, they no longer make things difficult [10]
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 However, when the red blood cells combined with CpG DNA encounter macrophages, they fumbled around—my death-free gold medal! That's right
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Researchers have found that after a large amount of CpG DNA is bound to the surface of red blood cells, it will cause the CD47 conformation on the surface of red blood cells to change, and the "don't eat me" signal is missing
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 Using the antibody CC2C6 to detect the expression of CD47 macrophages is also welcome.
Since there is no immune gold medal, then-"sucking~" That's it, when you have systemic inflammation (I wish everyone will not happen here), Your red blood cells are dead with many CpG DNA molecules
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As soon as CpG DNA is reduced, the immune system cools down; as soon as the red blood cells are reduced, anemia will come
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 The researchers also selected patients with anemia (n=9) and patients without anemia (n=39) from patients with severe sepsis for comparison.

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The results show that compared with patients without anemia, patients with sepsis with anemia have a higher level of red blood cells bound to CpG DNA, which also means that more red blood cells with CpG DNA will be eliminated together, causing the patient to develop Anemia
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The combination of CpG DNA will accelerate the phagocytosis of red blood cells by macrophages, causing anemia.
In fact, in the CpG DNA sweeping operation, red blood cells can help macrophages clear CpG DNA by "deathing generously" on the one hand, and avoid tissue damage caused by inflammation; On the one hand, it can also initiate an innate immune response, telling the immune system that "dangerous pathogens are coming or the body is damaged, so please react quickly!"
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 The researchers injected CpG DNA-bound red blood cells into mice, which caused systemic inflammation in the mice
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At 6 hours after the injection, the levels of IFN-γ and IL-6 in the plasma of the mice increased significantly, and the infiltration of neutrophils increased significantly
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In other words, red blood cells can alert the immune system by combining with CpG DNA, triggering an innate immune response
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The binding of red blood cells to CpG DNA can also cause inflammation.
In the process of research, the researchers also confirmed that red blood cells participate in the removal of CpG DNA are dependent on TLR9
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They found that in an inflammatory environment, the expression of TLR9 on the surface of red blood cells increased
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If TLR9 is missing, the red blood cells will not participate in the clearance of CpG DNA and will not be swallowed by macrophages
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 In general, although red blood cells have been confirmed in fish and birds to participate in immunity and defense against pathogens, in humans and other mammals, the immune function of red blood cells is still quite a mystery [2-4]
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This time, Mangalmurti's team discovered that the status of red blood cells in the human immune system far exceeds our imagination! In an inflammatory environment, red blood cells can recognize and bind free CpG DNA molecules in the blood through TLR9 on the cell surface, and then macrophages can remove red blood cells that bind a large amount of CpG DNA to relieve inflammation
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The combination of red blood cells and CpG DNA can also cause innate immune responses
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This study can be regarded as an explanation of a long-puzzling clinical phenomenon
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"Almost all intensive care patients develop anemia on the third day of entering the ICU," Mangalmurti said
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Researchers also suggest that if red blood cells can be prevented from binding to free CpG DNA in the blood, it may be able to solve the anemia problem that often occurs in patients with sepsis and new coronary disease
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Okay, now the red blood cells in the heart of Singularity Cake have another image-don't underestimate the immune function of red blood cells~ References: [1]11.
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Natural selection on the erythrocyte surface.
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[2]https:// NS.
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Red Blood Cells Homeostatically Bind Mitochondrial DNA through TLR9 to Maintain Quiescence and to Prevent Lung Injury.
Am J Respir Crit Care Med.
2018 Feb 15;197(4):470-480.
[4]Mangalmurti NS.
et al.
DNA binding to TLR9 expressed by red blood cells promotes innate immune activation and anemia.
Sci Transl Med.
2021 Oct 20;13(616):eabj1008.
[5]3.
Nakahira K, Kyung SY, Rogers AJ, Gazourian L, Youn S, Massaro AF , et al.
Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation.
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Schwarzenbach H, Hoon DS, Pantel K.
Cell-free nucleic acids as biomarkers in cancer patients.
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Zhang, M.
Raoof, Y.
Chen, Y.
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Itagaki, CJ Hauser,Circulating mitochondrial DAMPs cause inflammatory responses to injury.
Nature 464, 8]104–107 (2010).
[8]C.
Lood, LP Blancoet.
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Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease.
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22, 146–153 (2016).
[9]de Back DZ, Kostova EB, van Kraaij M, van den Berg TK, van Bruggen R.
Of macrophages and red blood cells; a complex love story.
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[10]PA Oldenborg, A.
Zheleznyak, YF Fang, CF Lagenaur, HD Gresham, FP Lindberg, Role of CD47 as a marker ofself on red blood cells.
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The author of this article | Zhang AidiAuthor of this article | Zhang Aidi