New study reveals how shedding DNA allows pro-inflammatory immune cells to quiet inflammation
The immune system’s first responders can reverse their own inflammatory response by shedding tiny pieces of their identity, according to a new study published May 22 in Nature Cell Biology.
When a tissue is injured or infected, a type of white blood cells called neutrophils flood the area to begin clearing out harmful material. This beneficial inflammation initiates the body’s natural healing process. But if this neutrophil infiltration is not eventually resolved, it can lead to harmful chronic inflammation disorders such as arthritis, inflammatory bowel disease and lupus.
University of Michigan faculty member Carole Parent, Ph.D., senior author on the study, investigates how these cells migrate so quickly and densely to sites of injury. A previous study from her lab demonstrated that, as neutrophils migrate, the first cells to respond secrete a molecule called leukotriene B4 (LTB4), which signals neighboring neutrophils to join the fight.
“These are the most abundant white blood cells in the body. They are the first line of defense, and they are ready for this very strong pro-inflammatory response,” explains Parent, a research professor at the U-M Life Sciences Institute, where her lab is located, and the Raymond and Lynne Ruddon Professor of Cancer Biology and Pharmacology at the Medical School. “But the pro-inflammatory response eventually subsides, neutrophils leave the site, and the tissue returns to normal. The question is: How do neutrophils go, fairly quickly, from a pro-inflammatory to an anti-inflammatory state?”
The team recently discovered that, along with packages of LTB4, neutrophils eventually secrete tiny trails of their own DNA as they travel. They wondered whether the secreted DNA fragments had a role in reversing inflammation.
The way I view it is that these cells are programmed to use everything they have to defend the body, including their own DNA.
A leak, not an explosion
Neutrophils are known to release their own DNA. One way they fight infection is by expelling all of their DNA to create a sort of net that can trap unwanted invaders — a process called NETosis. This explosion of nucleal material can contribute to inflammation and also results in cell death for the neutrophils.
“But in this case, the cells were still migrating while releasing DNA. They weren’t dying at all,” says Subhash Arya, Ph.D., a researcher in the Parent lab who led the study. “So we got the idea that this released DNA is not part of the inflammation process, that it’s actually helping with the resolution.”
Working with mouse models, the researchers measured the inflammatory response to a small skin injury over a period of two days. Under normal circumstances, inflammation peaked after about 12 hours and resolved within the next 36 hours. When they gave the mice an enzyme that degrades any loose DNA, however, the tissue remained inflamed after 48 hours — indicating that the secreted DNA must be present to relieve inflammation.
The team found that this leaked DNA was also serving as a bit of a trap, but not like the nets created through NETosis. Instead, the cells release just enough DNA for the LTB4 packages to stick to, leading to a local spike in the concentration of LTB4 in the inflamed region. When LTB4 hits a high enough concentration, it switches its signal — shutting off its inflammatory signaling and turning on anti-inflammatory signals that tell the neutrophils that their job is done and they need to leave.
This small loss of DNA does not affect the cells’ fate, in part because neutrophils do not divide to create new neutrophils, unlike many other cell types.
“In a way, neutrophils exist to die. They do not duplicate, so they don’t need to preserve their DNA to pass the way most cells in the body do,” Parent says. “The way I view it is that these cells are programmed to use everything they have to defend the body, including their own DNA.”
Top image: Neutrophils secrete DNA to reverse inflammation
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“Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation,” Nature Cell Biology. DOI: 10.1038/s41556-025-01671-4