A new LMU study shows how differently immune cells influence the formation of dangerous vascular deposits – and identifies miR-147 as a potential starting point for future therapies.

The heart and brain depend on a continuous supply of oxygen. Even brief interruptions in blood flow can have serious consequences – for example, when a vessel is narrowed or blocked by deposits.

Branching points in blood vessels are particularly vulnerable to such deposits. This is where fats such as cholesterol are more likely to accumulate in the vessel wall. The result is atherosclerosis – a gradual change in the arteries that increases the risk of heart attack and stroke.

The immune system is also involved in this process. Over many years, so-called macrophages – scavenger cells of the immune system – accumulate in the vessel wall. They take up fat, store it, and eventually die. What remains are cell debris and deposited fats, from which cholesterol crystals can form. These crystals destabilize plaques, promote blood clot formation, and thereby increase the risk of an acute vascular blockage.

Macrophages play a dual role

Researchers at LMU have now taken a closer look at the role played by different macrophages in atherosclerotic plaques. Using four-dimensional microscopic images of plaques in mice, the team led by Professor Andreas Schober and Dr. Maliheh Nazari Jahantigh at LMU University Hospital showed that not only lipid-laden macrophages but also lipid-free macrophages play a decisive role in shaping the disease process.

These lipid-free macrophages perform a dual function: on the one hand, they clear cellular debris, including DNA from dead cells, thereby limiting the formation of cholesterol crystals. On the other hand, they also attack the endothelium – the thin cell layer that lines and protects the inside of blood vessels. Inflammation, therefore, acts not only as a damaging force but also, in part, as a limiting one.

miR-147 as a potential therapeutic target

At the center of this balance is a small RNA molecule: miR-147. This microRNA is produced mainly in lipid-free macrophages. There, it helps the cells remove dead cell debris while also limiting damage to the endothelium. When miR-147 is absent, plaque formation, DNA deposits from dead cells, and cholesterol crystals all increase markedly.

According to the research team, this effect is due to miR-147 suppressing the production of the protein Galectin-3 in lipid-free macrophages. When Galectin-3 is released, it not only damages endothelial cells but also disrupts the macrophages’ energy supply. Without that energy, the cells clear away debris more slowly – a process that can further drive plaque formation.

“The inflammatory response in atherosclerosis is complex and includes both harmful effects and mechanisms that limit plaque growth,” says Dr. Nan Li, first author of the study. “This is precisely where a therapeutic opportunity lies: a treatment based on miR-147 could selectively influence inflammatory processes in atherosclerotic plaques and, in the long term, reduce the risk of heart attack and stroke.”