New research reveals that red blood cells function as critical immune sensors by binding cell-free DNA, called nucleic acid, present in the body’s circulation during sepsis and COVID-19, and that this DNA-binding capability triggers their removal from circulation, driving inflammation and anemia during severe illness and playing a much larger role in the immune system than previously thought. Scientists have long known that red blood cells, which are essential in delivering oxygen throughout the body, also interacted with the immune system, but didn’t know whether they directly altered inflammation, until now. The study, led by researchers at the Perelman School of Medicine, is published in Science Translational Medicine.
“Anemia is common, affecting about a quarter of the world’s population. Acute inflammatory anemia is often seen early after an infection such as parasitic infections that cause malaria,” says senior author Nilam Mangalmurti, an assistant professor of medicine at Penn. “For a long time we haven’t known why people, when they are critically ill from sepsis, trauma, COVID-19, a bacterial infection, or parasite infection, develop an acute anemia. These findings explain one of the mechanisms for the development of acute inflammatory anemia for the first time.”
Toll-like receptors (TLRs) are a class of proteins that play a key role in the immune system by activating immune responses like cytokine production. This study examined the red blood cells of about 50 sepsis patients and 100 COVID-19 patients and found that, during these illnesses, red blood cells express an increased amount of the specific TLR protein called TLR9 on their surface.
Results show that when the red blood cells bind too much inflammation-causing nucleic acid, they lose their normal structure, causing the body to not recognize them anymore. This leads immune cells, called macrophages, to “eat” them, taking them out of circulation in the body. When this happens it causes the immune system to become activated in otherwise unaffected organs, creating inflammation. This mechanistic discovery opens the door to research on how to block this specific receptor and create targeted therapies for autoimmune diseases, infectious diseases, and a whole host of inflammatory illnesses associated with acute anemia.
This story is by Kelsey Odorczyk. Read more at Penn Medicine News.