In a seminar Sept. 19, Michael Fessler, M.D., acting chief of the NIEHS Immunity, Inflammation, and Disease Laboratory discussed how the shuttling of cholesterol through the body impacts the immune response (see text box).
Cholesterol and immunity
Cholesterol is a fatty molecule necessary for making cell membranes. It also plays a role in production of vitamin D, hormones, and substances that help digest food. Yet having too much cholesterol in the body can lead to an increased risk of heart attack or stroke.
To remove excess cholesterol, immune cells called macrophages ingest and then export cholesterol from the cell, using transport proteins that specialize in carrying lipids, or fat molecules. From there, cholesterol is delivered to the liver and eventually exits the body in feces.
Fessler and members of his Clinical Investigation of Host Defense Group are especially interested in the stage when cholesterol enters the macrophage. Inside the macrophage, cholesterol activates a nuclear receptor called LXR, which leads to increased production of a protein known as toll-like receptor 4 (TLR4). TLR4 is a sensor for molecules shed from bacteria.
TLR4 is bound to areas of the outer cell membrane called lipid rafts, which are enriched in cholesterol. These rafts serve as platforms where immune receptors assemble and then send proinflammatory signals into the cell.
"We have genetically interrupted the cholesterol-trafficking pathway at several points as a strategy to uncover novel mechanisms of the innate immune response," Fessler said of his research. "Many of our studies have centered on lipid rafts."
Lipid rafts in the lung
One raft protein that Fessler studies, epithelial membrane protein 2 (EMP2), supports assembly of lipid rafts in the lung. He said that one of the most sought-after answers in lung research is how white blood cells known as neutrophils enter the lung and how they are controlled.
To tackle that question, Fessler used a knockout (KO) mouse model that lacked EMP2. The model was created by Carmen Williams, M.D., deputy chief of the NIEHS Reproductive and Developmental Biology Laboratory.
Fessler found that after these mice were exposed to different types of bacteria by inhalation, they displayed a significant decrease in the number of neutrophils recruited to the airspace of the lung.
He and Williams used this observation as the basis for a provisional patent application, which proposes to target EMP2 to prevent and treat lung disease. The discovery is a great example of the type of research that NIEHS scientists engage in every day.
"It is exciting, because others are studying EMP2 targeting antibodies for treatment in humans for cancer," Fessler said. "It may be an opportunity to repurpose these antibodies for blocking neutrophilic lung disease."