Enzyme Links Metabolic State to Inflammatory Response to Infection


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."

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Lung Inflammation Contributes to Metastasis


Pre-existing inflammation in the lungs may increase the risk that cancers beginning elsewhere will spread to the organ, according to new research from Weill Cornell Medicine.

Physicians have long noted an association between lung inflammation — seen in smokers or in people with lung diseases such as asthma, COPD and its subset emphysema, and pneumonia — and the development of lung tumors. But it's been unclear whether inflammation also increases the risk of pulmonary metastasis from other tumors. In their study, published Dec. 14 in the Proceedings of the National Academy of Sciences, the investigators reveal a mechanism by which this occurs, shedding light on how pre-existing lung inflammation creates an environment ripe for cancer spread to the organ. The findings may provide doctors new insights into how to treat and possibly prevent metastases.

"Identifying the molecular mechanisms by which pre-existing inflammation in the lungs enhances metastasis has huge clinical implications," said senior author Dr. Vivek Mittal, director of the Neuberger Berman Foundation Lung Cancer Laboratory and an associate professor of cell and developmental biology in cardiothoracic surgery and of cell and developmental biology at Weill Cornell Medicine. "Our research suggests that therapies could be designed to target this pathway to mitigate metastasis to the lung, particularly in cancer patients who exhibit lung inflammation due to exposure to cigarette smoke, bacterial infections, and other environmental pollutants."

Artist perception of lung with alveolar spaces and neutrophils

Artist’s perception of a lung showing alveolar spaces (white) and neutrophils (red). Some neutrophils are releasing the proteins Cathepsin G (CG) and Neutrophil elastase (NE) into the lung, which target and destroy the protein Thrombospondin 1 (Tsp-1). TSP-1 protects lung tissue from tumors; eliminating it enhances metastasis. Image credit: Puneeta Mittal (Lungs on Fire, Glazed ceramic panel)

Metastasis occurs when cells break away from a tumor and travel through the bloodstream or lymph vessels to other parts of the body. The lungs are a common site of metastasis from other cancers, including those of the bladder, breast, colon, kidney, prostate and brain. Lung metastases are hard to cure; in general, the five-year survival rate for patients with lung metastasis is near 30 to 40 percent.

"Metastasis is the major cause of death for people with cancer, so finding better ways to target metastatic tumors is critical," said Dr. Mittal, who is also a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

For their study, the researchers first induced inflammation in the lungs of mice by administering a bacterial toxin through the rodents' noses. They then injected the mice with melanoma cells, which grew into skin tumors and spread to the lungs.

"We found increased metastases in inflamed lungs compared to non-inflamed controls," Dr. Mittal said, "proving that inflammation plays a role in the spread of the cancer."

When they analyzed the inflamed lung tissue, the researchers found increased numbers of white blood cells called neutrophils, which release two enzymes into the lungs. These enzymes, neutrophil elastase (NE) and Cathepsin G (CG), target and destroy a protein known as Tsp-1, which protects lung tissue from tumors.

"Since Tsp-1 protects against metastasis, this creates an environment favorable to the spread of cancer," Dr. Mittal said.

Drs. Vivek Mittal and Tina El Rayes

Drs. Vivek Mittal and Tina El Rayes. Image credit: Mittal lab

The investigators say their findings could lead to new treatment strategies that focus on changing the environment inside the lungs that allows metastatic cancer cells to grow. A synthetic form of Tsp-1 that is resistant to the action of NE and CG, but contains characteristic cancer-suppressive properties could protect the lungs from metastatic cells, Dr. Mittal said.

Another option is a drug called Sivelestat, which is a known inhibitor of NE and used to treat patients with acute lung injury. Importantly, the investigators found that it also inhibits CG, making it an ideal therapeutic choice. Both of these strategies would allow Tsp-1 to function normally and target cancer cells that travel to the lungs, preventing metastasis.

"The preclinical data obtained from these studies will generate unique translational opportunities, and may lead to the design of future clinical trials for cancer patients who exhibit pulmonary inflammation," said first author Dr. Tina El Rayes, a postdoctoral associate who finished her doctorate from the Weill Cornell Graduate School of Medical Sciences with this study.

Dr. Mittal believes that an intervention against inflammation-driven cancer spread can lead to the development of an anti-metastatic therapy. He is leading a preclinical study that investigates whether dual inhibition of NE and CG can effectively prevent breast cancer from metastasizing to inflamed lungs.

Dr. Mittal's research also points to the need to understand whether inflammation in other organs might contribute to the spread of cancers as well.

"It should be applicable to any tumor with metastatic potential," he said. "It's really a hopeful finding for cancer treatment."

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