Researchers at Yale University School of Medicine have identified a way to suppress the daily fluctuations in the activity of key immune cells known as neutrophils. The study, to be published December 12 in the Journal of Experimental Medicine (JEM), suggests that inhibiting these fluctuations could prevent neutrophils from causing excessive tissue damage during daylight hours, a phenomenon that may underlie the fact that heart attacks in the early morning are more damaging than heart attacks suffered at night.
Neutrophils provide the first line of defense against microbial infections and tissue injury. However, their efforts to promote inflammation and kill injured or infected cells can result in the death of nearby healthy cells. In fact, neutrophils have an internal clock that makes them more active and prone to cause tissue damage during the daytime. This could help explain the long-standing observation that heart attacks in the early morning have more severe consequences than heart attacks at night, because excessive neutrophil activity contributes significantly to the size of myocardial infarcts and long-term reductions in cardiac function.
Professor Andrés Hidalgo and colleagues at Yale University School of Medicine previously found that mice whose neutrophils lack this internal clock do not show daily peaks in neutrophil activity, but are still able to fight off bacterial and fungal infections. "We thought that targeting the neutrophil clock could provide a simple and effective means to blunt the toxic activity of these cells during myocardial infarctions, without compromising antimicrobial defense," Hidalgo says.
In the new JEM study, Hidalgo and colleagues performed a series of experiments to confirm that, like in humans, mice suffer greater cardiac tissue damage after a heart attack in the early morning, and that this is due to enhanced neutrophil activity at this time of the day. Treating mice with a drug that inhibits the neutrophil clock reduced the amount of myocardial tissue damage after a heart attack and helped to preserve heart function over the following days and weeks.
The drug, known as ATI2341, targets a receptor protein on the surface of neutrophils and switches the cells into a less active mode usually only seen at night. In their active, daytime mode, neutrophils accumulate around the edge of the initial wound caused by a heart attack, where they are poised to damage neighboring healthy cardiac tissue and extend the size of the injury. In night mode, however, neutrophils accumulate in the center of the initial wound, well away from the surrounding, healthy tissue.
ATI2341 also protected mice from several other types of neutrophil-induced tissue damage but, crucially, did not impair the animals' ability to fend off bacterial and fungal infections.
"Our study demonstrates that pharmacological delivery of a drug that activates a receptor on the surface of neutrophils induces their transition to a night-like, permissive state that alleviates the inflammatory response without interfering with antimicrobial defense," Hidalgo says. "This therapeutic strategy provides an advantage when compared with other approaches that target neutrophil function or numbers, which compromise the capacity of the host to control infections or to promote wound healing."
Aroca-Crevillén et al. 2025. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20250240?PR
