Chronic inflammation can quietly sabotage the body’s own repair crew. A new UNC-Chapel Hill study shows how key immune cells get stuck in harmful states and points to ways scientists might one day reset them.
Chronic inflammation does more than cause lingering pain or swelling. It can quietly sabotage the body’s own repair crew, according to new research from the University of North Carolina at Chapel Hill.
In a study using transparent zebrafish, UNC-Chapel Hill scientists watched immune cells called macrophages respond to injury over time and discovered how long-lasting inflammation can lock them into harmful, dysfunctional states. The research, published in Nature Communications, helps explain why chronic inflammation is tied to diseases such as cancer, diabetes, heart disease and neurological disorders, and it highlights new molecular targets that could one day help restore healthy healing.
Macrophages are frontline defenders of the immune system. They help spark inflammation to fight infections and clear debris, but they also play a crucial role in repairing damaged tissues once the immediate threat has passed. For years, researchers have described these as separate modes, often simplified as “attack” versus “repair.”
The team, led by Celia Shiau, an associate professor of biology, microbiology and immunology, found that this tidy division breaks down when inflammation never really turns off.
Using live zebrafish embryos, the researchers created a tail muscle injury and followed individual macrophages in real time as inflammation persisted, either because of a genetic mutation or a long-lasting infection. Zebrafish are a powerful model for this kind of research because their embryos are transparent, allowing scientists to see cells move and change inside a living organism.
The team discovered that under chronic inflammatory conditions, macrophages lose their normal flexibility, or plasticity. Instead of switching cleanly from an inflammatory mode to a repair mode, many cells became stuck in hybrid states. They continued to promote inflammation but failed to properly clear damaged cells or support tissue repair, even though they still carried some of the genetic instructions needed for healing.
To understand what was going wrong at the molecular level, the researchers looked at which genes were turned on or off in these cells. They found that chronically inflamed macrophages suppressed a key repair-associated gene called mrc1b. This gene is the zebrafish version of the human Mrc1 gene, which encodes the mannose receptor CD206, a well-known marker linked to tissue-repairing macrophages.
The team also identified a new molecular sign of macrophages that are truly engaged in repair. In healthy healing conditions, a subset of macrophages involved in tissue repair accumulated an enzyme called cathepsin K. This enzyme helps break down proteins inside and outside cells. In chronically inflamed macrophages, that buildup of cathepsin K did not occur, making the enzyme a useful marker for distinguishing repair-promoting cells from those stuck in a dysfunctional state.
Together, these findings show how chronic inflammation can derail muscle repair by rewiring macrophages so they keep fueling damage instead of fixing it.
The study also introduced a powerful new genetic tracking tool that lets scientists watch macrophages flip into inflammatory states in real time inside a living animal. The researchers engineered a system in which macrophages brighten by increasing a fluorescent protein when they become inflamed. That glow allowed the team to follow immune cell activation and behavior over long periods, capturing dynamic states that traditional snapshots of tissue could easily miss.
Shiau described what it was like to see the immune response unfold in living organisms.
“Tracking immune cells as they respond to injury in real time was like watching an action-packed sports game unfold,” she said in a news release. “Where some macrophages are both causing inflammation and starting repair at the same time – rewriting what we thought were separate roles.”
By revealing that chronic inflammation can trap macrophages in maladaptive hybrid states and by pinpointing specific genes and enzymes involved, the research opens new avenues for research on how to reset or reprogram these cells.
“By understanding how chronic inflammation rewires macrophages molecularly and behaviorally, we not only can better understand disease but also move toward engineering immune cells with more customizable, desirable functions,” Shiau added.
That kind of immune engineering is still in the future, but the implications are wide-ranging. Many major diseases, from atherosclerosis and obesity to Alzheimer’s disease and certain cancers, involve chronic inflammation and dysfunctional immune responses. If scientists can learn to nudge macrophages back into effective repair modes, it could improve recovery after muscle injuries and potentially benefit other tissues as well.
Next steps for the field include testing whether similar macrophage states and molecular markers appear in mammals, including humans, and exploring ways to manipulate genes like Mrc1 or enzymes like cathepsin K to restore healthy tissue repair. The new live-imaging and tracking tools developed in zebrafish provide a blueprint for studying immune cell behavior in other systems, bringing researchers closer to therapies that can calm harmful inflammation without shutting down the body’s ability to heal.