Immune Cells’ Role as Quality Control Boosts Tissue Health

One of the primary functions of specialized white blood cells called macrophages is to fight off disease-causing pathogens. But they also live in organs like the heart that are not typically exposed to infection. A new Yale study shows why macrophages are important in this context and reveals how certain tissues regulate the number of macrophages they contain.

Andres Hidalgo, PhD, professor of immunobiology, studies the physiological role of immune cells beyond preventing infection. Previous research in his laboratory has revealed that macrophages also support cardiac function by eliminating metabolic waste products.

Now, in a Science Immunology study published Sept. 4, his team has discovered that this process is not exclusive to the heart. It’s also found in other tissues that require large amounts of energy to function, including muscle tissue.

The researchers uncovered a mechanism that controls macrophage abundance, and they found that blocking this mechanism in tissues leads to their dysfunction. Understanding the processes underlying how macrophages promote organ function could lead to clues for how to prolong their health and to develop new therapies that promote healthy aging.

“Some organs like the heart need a lot of energy,” says Hidalgo, the study’s principal investigator. “The immune system acts as quality control that makes sure an organ like the heart can pump for 80 years straight or more.”

The heart, Hidalgo says, is full of macrophages. But unlike other organs, such as the skin or lungs, it is not exposed directly to the outside environment where it may come in contact with infectious invaders. Hidalgo wondered if the macrophages were there instead to defend against a different, internal kind of stressor.

To maintain its function, the heart requires a lot of energy. It beats between 60 and 100 times per minute, on average, and its work is nonstop.

“It’s like the heart is running a marathon all the time, even if you’re just sitting there,” he explains. “And it needs to do that for hopefully the 80, 90 years that you are going to be alive.”

To sustain life, the mitochondria in the heart’s cells are continuously converting fuel into energy. But this non-stop process generates a considerable amount of waste, including mitochondria that become damaged over time. Back in 2020, Hidalgo’s team discovered that macrophages in the heart play a crucial role in removing defective mitochondria. Without macrophages, they found, waste accumulated and the heart became inflamed and eventually began to dysfunction.

In the latest study, Hidalgo’s team tracked mitochondria as they moved between tissues—16 different kinds—and macrophages. They found that the uptake of defective mitochondria by the immune cells primarily occurred in tissues that rely on oxidative respiration, or the process of using oxygen to generate large amounts of energy. Tissues that require a lot of energy tend to rely on oxidative respiration.

In particular, the researchers observed this process in the heart, muscles, and brown adipose tissue, a specialized type of fat that generates heat to keep the body warm. All of these tissues transferred waste to macrophages in membrane-bound packages. This packaging might help prevent defective mitochondria from releasing inflammatory signals into the body as they are transferred to the macrophages, the team proposes.

The researchers also created models in which they added or removed mitochondria from the tissues and observed how the immune cells responded to these changes. They found that the level of mitochondrial activity in a tissue was linked to the number of macrophages it contained. Tissues with higher numbers of mitochondria generating more energy, for example, also had greater macrophage abundance.

“When we looked across organs, what we discovered was that the number of macrophages in a tissue was almost perfectly aligned with the respiratory capacity of that tissue,” Hidalgo says. “This was surprising because it is rare in biology to find two parameters that align so closely.”

Next, the researchers wondered which cells were driving the changes in macrophage abundance. Prior research shows that several molecules stimulate macrophage production, including colony-stimulating factor 1 (CSF1). Through single-cell RNA sequencing of cells across tissues, they found that CSF1 was primarily produced by cells called fibroblasts, which make and maintain our connective tissues.

When the researchers used an antibody to block CSF1 in animal models, macrophages disappeared from the tissues. This confirmed that fibroblasts regulate macrophage abundance by producing CSF1.

“Fibroblasts, in a way we haven’t defined yet, sense the respiratory capacity of the organ,” Hidalgo says.

Furthermore, the team found, blocking macrophages in specific tissues in animal models ultimately led to the dysfunction of those tissues. Brown adipose tissue became less effective in producing heat, muscle cells became weaker, and the pumping capacity of the heart was reduced.

The study highlights the role of our immune system as a “quality control system” that maintains organ function. It could also help scientists understand the underlying processes when they fail to work properly.

Our organs, for example, don’t work as well as we age. Hidalgo’s team is now exploring how the processes regulating macrophage abundance in relevant tissues change over the lifespan, and if changing the number of macrophages impacts their function. They hope their work can help clarify why some individuals might be healthier in their later years than their peers, as well as help scientists learn how to engineer new therapies that promote healthy aging.

“We want to see if this frailty that comes with age is really controlled by macrophages,” Hidalgo says. “And if so, could we supplement macrophages to extend the health of the organs we care about—the eyes, the brain, the heart, the muscles?”