As the roughly 30 trillion human red blood cells cruise the bloodstream and supply tissues with oxygen, they may also be doing something biologists did not expect: scanning for signs of infection and injury. According to new findings that would dramatically expand their roles, red blood cells snare suspect DNA from microbial invaders or damaged tissue and warn the immune system of danger.
“This is a new immune function for red blood cells that is quite exciting,” says pathologist Steven Spitalnik of Columbia University. “I’m thinking of 17 different applications.” The findings suggest, for instance, the immune role is linked to the anemia that often afflicts people with sepsis, COVID-19, and other conditions—and point to ways to combat it.
As human red blood cells mature, they lose all of their DNA and organelles. The cells’ stripped-down structure inspired the traditional view that “they are blah, inert bags of hemoglobin,” able to do little beyond ferry oxygen, says pulmonary and critical care physician Nilam Mangalmurti of the University of Pennsylvania Perelman School of Medicine, whose team made the DNA-capturing discovery. Over time, however, scientists have uncovered other functions for the cells, such as managing blood levels of nitric oxide, the molecule that spurs blood vessels to dilate.
In principle, red blood cells would make good protectors of the human body—not only because of their numbers, but also because they penetrate the nooks and crannies of organs and tissues. Researchers have found that some vertebrates such as fishes and birds enlist red blood cells for defense—and even sic them on pathogens. But in humans and other mammals, evidence for an immune role remained inconclusive.
In a 2018 study, Mangalmurti’s team found a clue. The researchers determined that red blood cells harbor a type of molecular sensor, known as toll-like receptor 9 (TLR9), that recognizes and sticks to DNA molecules containing pairs of the nucleotide bases cytosine and guanine. Damaged human cells release such DNA, and the DNA of bacteria and other pathogens is also rich with these cytosine-guanine duos, or CpG motifs. They incite a strong immune system reaction that researchers ascribed primarily to white blood cells, which also sport TLR9.
But Mangalmurti and colleagues’ latest research, published this week in Science Translational Medicine, suggests red cells take part as well. In the test tube, the researchers traced what happens when human red cells latch onto CpG-containing DNA. Small amounts of the DNA didn’t appear to affect the cells, but larger amounts caused them to scrunch up, suggesting they were responding to the stimulus.
That red blood cell response could alert the immune system to foreign DNA or tissue damage, the researchers propose. It could help drive a less beneficial immune response as well. Mangalmurti and colleagues found that giving mice red blood cells that had captured CpG-containing DNA triggered bodywide inflammation. In humans, such inflammation is a hallmark of sepsis and can erupt because of injuries or other illnesses, including COVID-19.
Red cells’ sentinel role could also help explain a common complication for hospitalized patients. “Almost all critical care patients are anemic by their third day in the ICU [intensive care unit],” Mangalmurti says. As blood passes through the spleen, immune cells called macrophages ordinarily devour old and damaged red blood cells. Healthy red blood cells can avoid being culled if they display a particular “don’t eat me” protein on their surface. But in the test tube, the researchers found, an encounter with CpG-carrying DNA causes the cells to conceal the portion of this protein that rebuffs macrophages.
The team observed the consequences of this change in mice. When the researchers transfused red blood cells into the animals, macrophages in their spleens gobbled cells that had been exposed to CpG-laden DNA, but ate fewer red blood cells that hadn’t encountered the DNA. The researchers also found red blood cells from patients with sepsis and anemia sported more of the DNA than did cells from patients with only sepsis. Patients with COVID-19 and anemia showed the same disparity compared to patients who only had COVID-19, suggesting high levels of the DNA provoke destruction of the cells.
“We can now say that red blood cells have an immune function” in humans and other mammals, Mangalmurti says. Most of the time, she suggests, the cells serve as janitors for normal cleanup duties, sweeping up potentially harmful DNA that leaks into the circulation from the many body cells that die every day. But during an infection or after an injury, this DNA may flood the bloodstream. The red blood cells then sacrifice themselves by encouraging macrophages to eat them, alert the immune system, and trigger inflammation. If macrophages consume too many red blood cells, however, anemia may result.
Drugs that prevent the wayward DNA from adhering to TLR9 on red blood cells could treat the anemia, Mangalmurti proposes. She and her colleagues are also investigating whether DNA stuck to red blood cells could help diagnose infections.
The researchers “should be commended for the rigor of their experimental approach,” says clinical pathologist Robertson Davenport of the University of Michigan, Ann Arbor. But he adds that further data is necessary to confirm that red blood cells are essential for mammals’ immune defense.
Davenport adds that anemia in patients with sepsis can result from several causes and there’s little evidence that excessive macrophage consumption of red blood cells is responsible. Then again, he notes, “We haven’t looked very carefully.”
In time, Mangalmurti is convinced, biologists will look at these oxygen carriers in a whole new light.
