Understanding the biology of macrophages

When macrophages operate normally, they sense pathogens like viruses and bacteria and launch an immune response. Dr. Chen studies a protein on the surface of macrophages that, in addition to sensing pathogens, senses the body’s own molecules, including a modified form of low-density lipoprotein (LDL). Though it is often referred to as the “bad” cholesterol, LDL carries most of the cholesterol in blood and is essential for a healthy human body. Too much of it, however, can lead to heart attacks, strokes and other adverse events. LDL is particularly dangerous when it comes into contact with an unstable molecule called reactive oxygen species (ROS). When LDL and ROS react, they cause oxidized LDL cholesterol to build up in the body.

Generally, the cells in our bodies try to prevent harmful cholesterol from building up. Macrophages help by absorbing and clearing lipids—a process critical to maintaining human health. However, sometimes, they get stuck trying to perform their normal functions. “When a normal macrophage is engulfing cholesterol, it will try to prevent accumulation of lipids,” Dr. Chen said. “But as macrophages engulf more and more lipids, they can get stuck inside of blood vessels. We don’t fully understand why there is so much cholesterol and other lipids stuck inside these macrophages.”

Researchers know that these cells build up in our blood vessels, but they hope to learn more about how to slow down the process and clear the cells that contain too many lipids. “We have to understand more about the mechanism—how they produce the ROS and lead to an oxidized form of LDL production and how the cells end up taking up too many lipids,” Dr. Chen said.

Because of this, it has been difficult for researchers to discover and develop a better treatment for patients. “There is currently no way to prevent the process or make it go away,” Dr. Chen said. “The major reason is because we don’t understand the mechanism and what leads to cell accumulation in blood vessels. We focus on studying the biology of macrophages and how, for example, the oxidized form of LDL activates macrophages and mounts a response, eventually causing heart disease.”

Connecting the immune system with metabolism

To do this, the body’s immune system and metabolism are engaged in a delicate balance to manage lipids. Cells require normal amounts of cholesterol and fatty acids to perform their usual functions, but a trigger like oxidized LDL can drastically alter a person’s immune response. When the immune system fights bacteria or a virus like the flu, it prompts an immune response with recognizable reactions, like a fever. However, the same is not true when it faces our own molecules, like oxidized LDL. Though the immune system is activated, its response isn’t strong enough to prompt a noticeable reaction because no bacteria or viruses are involved—instead, macrophages are. Over time, this immune response builds until one day, it triggers a cardiac event like a heart attack or stroke.

Dr. Chen seeks to understand why, over time, these macrophages are continually activated and keep absorbing lipids. “My hypothesis is that the metabolism is altered,” he said. “We study macrophages, and we try to answer the question of why they are chronically activated during atherosclerosis. If we figure out why and how to reverse the process, we could save millions of lives by reducing atherosclerosis, heart attack and stroke. That’s our ultimate goal.”

How collaboration furthers lifesaving research

Dr. Chen often collaborates with VBRI Assistant Investigator Ze Zheng, MBBS, PhD, who studies the liver, which is critical to removing extra cholesterol from the body. “There are tons of ways for us to acquire cholesterol,” Dr. Chen said. “You can eat meat and acquire cholesterol. But even if you’re vegan, you still get cholesterol because your cells contain all of the enzymes needed to make it. However, there is no enzyme that can eliminate cholesterol; the only way to eliminate it is through the liver.”

Macrophages tell the liver when there is too much cholesterol in the body. The liver then turns cholesterol into a bile acid and excretes it through the feces, which is the only way to eliminate extra cholesterol from the body. Dr. Chen seeks to understand what happens in macrophages to accumulate extra cholesterol, while Dr. Zheng is interested in understanding what happens in liver cells and how the metabolism manages extra cholesterol.

“This cross collaboration is exactly why I love VBRI,” Dr. Chen said. “It is an excellent research environment and one of the top institutes in the country.” He believes that his collaboration with Dr. Zheng’s lab helps to bolster trust among researchers and lead to new ideas and potentially, lifesaving treatments for patients.

“To be an excellent researcher, you have to realize that you’re not alone,” he said. “Every investigator at VBRI works together as an excellent team.”

About the expert: Yiliang Chen, PhD, is an assistant investigator at Versiti Blood Research Institute and an assistant professor of medicine in the Division of Endocrinology and Molecular Medicine at the Medical College of Wisconsin.