In the aftermath of a heart attack, the immune system rapidly targets the injured heart to remove damaged cells and trigger repair. But when this response lingers too long, it can fuel scarring that ultimately weakens the heart. Now, researchers at Temple University’s Lewis Katz School of Medicine (Katz) have found that blocking a stress-related signal in immune cells—the β2-adrenergic receptor (β2AR)—enhances the cells’ ability to clear debris, limits scarring, and improves heart function.
The new study, published online January 14 in the journal Theranostics, is the first to show that dialing back β2AR activity in immune cells helps the heart recover after a heart attack by clearing inflammation more efficiently.
“Our findings reveal a previously unrecognized target for improving tissue repair after cardiac injury,” said Douglas G. Tilley, PhD, Professor in the Aging + Cardiovascular Discovery Center and Associate Dean of Faculty Affairs at Temple’s Lewis Katz School of Medicine and senior author on the new paper. “We now have a new avenue to the exploration of novel heart repair therapies.”
Scientists have long known that stress hormones such as adrenaline and noradrenaline influence immune behavior by binding to β2AR and similar receptors. In many tissues, β2AR activation can either amplify or dampen inflammation, depending on the context. The heart, however, presents a unique environment, where the balance between inflammation and repair after injury is especially delicate.
Dr. Tilley’s team, led by postdoctoral fellow Tapas K. Nayak, PhD, set out to understand the role of β2AR signaling in myeloid-specific immune cell responses to acute cardiac injury following heart attack. Myeloid cells, which include neutrophils, monocytes, and macrophages, are the primary coordinators of immune activity immediately following injury to the heart.
The researchers carried out experiments in mice genetically engineered to no longer express β2AR in myeloid cells. They tracked heart function, immune cell behavior, gene expression, and tissue scarring following the induction of heart attack and used targeted gene-silencing techniques to pinpoint the underlying mechanisms.
Mice without β2AR in their myeloid cells exhibited stronger heart function and had significantly less scarring after sustaining damage to the heart. While immune cells initially rushed to the injured tissue in similar numbers, these mice cleared inflammatory neutrophils more quickly than their wild-type counterparts. “Their macrophages were better at efferocytosis—the cleanup process that removes dying cells,” Dr. Tilley explained.
This enhanced cleanup was linked to higher levels of annexin A1, a protein that promotes the resolution of inflammation. The researchers uncovered a molecular switch behind this effect: β2AR signaling normally boosts certain microRNAs that suppress annexin A1. Without β2AR, this suppression was lifted, allowing macrophages to clear debris more efficiently. When annexin A1 was experimentally reduced in myeloid cells lacking β2AR, the protective benefits disappeared.
“By improving the body’s natural ability to resolve inflammation, targeting β2AR signaling in immune cells could help limit tissue damage and preserve heart function after a heart attack,” Dr. Tilley said.
Future work will explore whether drugs that fine-tune β2AR signaling—or boost annexin A1 activity—can safely promote heart healing in people. Drugs capable of dampening β2AR, known as beta-blockers, are already on the market, providing an opportunity for rapid translation into clinical studies. If successful, this approach could complement existing treatments by helping the heart heal more effectively, not just survive.
Other researchers who contributed to the study include Anamika Bajpai, Viren Patwa, Rhonda L. Carter, Nitya Enjamuri, Erhe Gao, and Sudarsan Rajan, Aging + Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University; and Yang K. Xiang, Department of Medicine, University of California at Los Angeles.
The research was supported by grants from Veterans Affairs and the National Institutes of Health, including a project headed by Dr. Tilley as part of a larger Program Project Grant exploring mediators of cardiac injury and repair, with additional postdoctoral fellowship funding by the American Heart Association.