An enzyme that stimulates the breakdown of fats in immune cells helps trigger inflammation, or an immune response to pathogens, a new study by Weill Cornell Medicine researchers suggests. The findings enhance scientists' understanding of the connection between metabolism and inflammation, and may offer a new approach to treat dangerous infections such as pneumonia.
In their study, published July 25 in Nature Medicine, the team showed that the mitochondrial enzyme NOX4 regulates the activation of an inflammation-triggering protein complex called an inflammasome. It does this by increasing the levels of a key enzyme in fat breakdown, a process called free fatty acid oxidation.
"Inflammation is an important immune response to pathogens, but when it becomes chronic or if the response is too strong, it can hurt the patient," said senior author Dr. Augustine M.K. Choi, interim dean of Weill Cornell Medicine and Weill Chairman of the Weill Department of Medicine. "We knew that people with obesity-induced metabolic diseases, like diabetes, have an abnormal response to infectious agents, and in this paper we were able to make a connection between the two."
The connection is found in mitochondria, which in addition to being the cell's powerhouse plays an important role in the cellular stress response. The mitochondrial enzyme NADPH oxidase-4 (NOX4) produces reactive oxygen species (ROS), chemically reactive molecules that kill pathogens and signal that the cell is under stress, among other cellular responses. "Since NOX4 was linked to both diabetes and immunity, we wanted to understand what it was doing at the interface between the two," said lead author Dr. Jong-Seok Moon, a postdoctoral fellow in Dr. Choi's laboratory.
In mice infected with pneumonia, the researchers found a reduced inflammatory response and reduced mortality in mice lacking NOX4. Human immune cells lacking NOX4 also showed a reduced inflammasome response when presented with chemicals that normally provoke the cells. The group showed that these responses were lacking because there was a corresponding failure to increase levels of a key enzyme for mitochondria fatty acid oxidation, called CPT1a. Without this NOX-4-dependent boost in fat breakdown, the inflammatory response was blunted.
Currently, a drug that inhibits NOX4 is in phase 2 clinical trials to treat diabetic nephropathy, a condition where blood vessels in the kidney are destroyed. The team showed that the drug, GKT137831, was also effective in reducing inflammasome activation in mice, including in the pneumonia model. "Since this drug is already in phase 2 clinical trials, we think it is a good candidate for additional research as a treatment for patients with metabolic inflammation and infectious disease as well," said Dr. Choi, who is also physician-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center. "With the number of people affected by type 2 diabetes and obesity growing each year, we need to understand the link to inflammation and infection so we can treat these patients more effectively."