The Autophagy Paradox


Could a process that's normally essential to life be a root cause of COPD?

Known as autophagy, it's a mechanism in which cells conserve energy and nutrients by consuming damaged or unneeded organelles — the tiny structures that perform various functions within each cell. "When people are starving, autophagy is critical," Dr. Choi explains. "But it also regulates inflammation, cell growth and many other processes." For example, in 2010 Dr. Choi and his team reported in
Nature Immunology that autophagy confers a potent anti-inflammatory effect in acute inflammatory conditions. "The complexity of this," he notes, "is highlighted by the fact that in some other diseases of the lung, like pulmonary hypertension, autophagy is a good thing."Chronic obstructive pulmonary disease (COPD) kills some 130,000 Americans every year — including, in February, the actor Leonard Nimoy, beloved by millions for playing Mr. Spock on TV's "Star Trek." While the disease — the third-leading cause of death in the United States — is strongly associated with smoking, its underlying causes have never been clear, and effective treatments have proven elusive. "Right now, all you can do is mitigate it," says Dr. Augustine Choi, the Sanford I. Weill Chairman of the Weill Department of Medicine. "There's no cure." But Dr. Choi may have found an important clue to how COPD happens—and surprisingly, it's a process that is normally fundamental to our survival.

But that is not the case in chronic pulmonary disease. Dr. Choi and his team had previously found higher rates of autophagy in the lungs of people with COPD, and they have demonstrated that this leads to cell death that ultimately affects pulmonary function. In a paper published last fall in the Journal of Clinical Investigation, they explained that when cigarette smoke enters the air sacs in a smoker's lungs, it harms their mitochondria, the organelles that serve as cellular power plants. The cells are prompted to destroy their damaged mitochondria, but then they become unstable and are killed off. "The obvious question then is, can we block autophagy with new chemical inhibitors or drugs?" Dr. Choi says. "This has significant therapeutic implications, for sure, but we have to be cautious and systematic about how and when to target the autophagy in COPD."

Autophagy was first described in the 1960s, and for the next few decades it was the province of cell biologists, who studied the process in yeast. It was only within the last 10 to 15 years, Dr. Choi says, that scientists began to investigate autophagy in humans. And since 2008, when his team first published findings about autophagy in lung tissue from COPD patients, other researchers have begun to investigate its role in a host of other human diseases. "We got into the game a bit earlier than most people," Dr. Choi says. "Now you can't pick up a journal without seeing a paper on autophagy. The cancer guys have been doing a lot of autophagy work. Alzheimer's, Parkinson's, infectious disease—I could go on and on." At Weill Cornell Medicine alone, researchers have found links between autophagy and gynecologic cancers, female genital tract infection, pancreatic cancer, metabolic diseases, and kidney failure.

Drs. Augustine Choi, Ilias Siempos and Mitsuru Imamura

Autophagy investigators: Dr. Augustine Choi (center) with research fellows (left) Dr. Ilias Siempos and Dr. Mitsuru Imamura. Photo credit: John Abbott

Over the years, Dr. Choi has seen attitudes toward COPD shift significantly. It was once considered hopeless, he says, and research funding was limited in part because patients with diseases linked to smoking were not seen sympathetically. But while COPD patients may be haunted by the stereotype of the unrepentant lifelong smoker, the disease can develop decades after people quit, as in Nimoy's case. It can also strike non-smokers, for reasons that are still unknown. "The incidence of COPD not related to cigarette smoking is increasing," Dr. Choi says "Whether it's pollution, particulate matter in the environment, infections or a virus— we don't know." And that's just one of the many questions Dr. Choi and his colleagues are working to answer. They are also looking into how protective mechanisms in the lungs could offset autophagy, and they're trying to find a way to detect COPD with a simple blood test rather than a CAT scan.

Among the Weill Cornell Medicine researchers working on autophagy is Dr. Choi's wife, Dr. Mary Choi. An associate professor of medicine in the Division of Nephrology and Hypertension, she is leading investigations into its role in diseases of the kidney. She has found that impaired autophagy could lead to kidney fibrosis, a common feature in kidney failure and diabetic nephropathy — which means that therapies targeting autophagy could potentially restore kidney function. The couple came to Weill Cornell Medicine in 2013 from Boston, where both were on the faculty at Harvard Medical School and he was chief of pulmonary and critical care medicine at Brigham and Women's Hospital. There, as at Weill Cornell Medicine, patient care was a major aspect of his work. "Seeing patients gives you focus, and it helps you identify the questions that we need to address," Dr. Choi says. "Patients are what it's all about — you're trying to make an impact on human disease."

— Amy Crawford

This story first appeared in Weill Cornell Medicine, Vol. 14, No.2.

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Organ damage: In a mouse model of a kidney fibrosis, epithelial cells show evidence of autophagy (the green spots marked by arrows), which was mounted as a defense against scarring (seen in red).
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Study Finds Lipid Mediator Associated with Good Cholesterol Promotes More Than Just Good Heart Health


High-density lipoprotein (HDL) is often referred to as "good" cholesterol because it transports fat molecules out of blood vessels, protecting against stroke and heart disease. Now, researchers at Weill Cornell Medical College have discovered that HDL in blood also carries a protein that powerfully regulates immune function. Together they play an important role in preventing inflammation in the body.

In the study, published June 8 in Nature, the investigators found that a lipid molecule called sphingosine 1-phosphate (S1P) that is bound to HDL suppresses the formation of T and B immune cells in the bone marrow. In doing so, HDL and S1P block these cells from launching an abnormal immune response that leads to damaging inflammation, a hallmark of many disorders including autoimmune diseases, cardiovascular disease and neuroinflammatory disease, such as multiple sclerosis.

"Our study shows that S1P that is bound to HDL helps prevent inflammation in many tissues," said senior investigator Dr. Timothy Hla, director of the Center for Vascular Biology and a professor of pathology and laboratory medicine at Weill Cornell. "When there is less S1P that is bound to HDL in blood, there are more B and T cells that can be activated to produce unwanted inflammation."

Dr. Hla has been studying S1P for more than two decades. He discovered that it is a key regulator of vascular function, and that about 65 percent of S1P in blood is bound to apolipoprotein M (ApoM), a member of the lipoprotein family, within the HDL particle. But until this study, the researchers did not know what specific function HDL-bound S1P served.

The team, including first author Dr. Victoria Blaho, an instructor in pathology and laboratory medicine, and researchers from the National Institutes of Health and Stanford University, studied mice that lacked HDL-bound S1P.

Dr. Timothy Hla

Dr. Timothy Hla. Photo credit: Carlos Rene Perez

Mice lacking HDL-bound S1P developed worse inflammation in a model of multiple sclerosis. The reason for this, the investigators found, is that HDL-bound S1P suppresses the formation of T and B immune cells in the bone marrow. While both immune cells help fight infection, an overabundance of these cells can also trigger unwanted inflammation.

The findings help explain why blood HDL levels are such an important measure of cardiovascular health, Dr. Hla said.

"Blood HDL levels are associated with heart and brain health — the higher the HDL in blood, the less risk one has for cardiovascular diseases, stroke, and dementia," Dr. Hla said. "The corollary is that the lower the HDL, the higher the risk of these diseases." Blood levels of ApoM and S1P have not been studied in these diseases.

The findings further suggest that molecules that mimic HDL-bound S1P could be useful in reducing damaging inflammation that has gone awry, Dr. Hla said. Such molecules are not known and will need to be developed in the future.

However, a related S1P1 receptor inhibitor called Gilenya, has already been approved for use in multiple sclerosis, a condition in which the immune system attacks nerve fibers due to unwanted inflammation, Dr. Hla said.

"The unique function of HDL-S1P could be further exploited for innovative therapeutic opportunities," he said.

For this research, Dr. Blaho received funding from the National Institutes of Health (F32 CA14211), the New York Stem Cell Foundation (C026878) and the Leon Levy Foundation (supported through the Feil Family Brain and Mind Research Institute). Dr. Hla received funding from the NIH (HL67330 and HL89934), as well as through Fondation Leducq.

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Left: T and B cells are types of white blood cells that develop from stem cells (progenitor cells) in the bone marrow. When HDL (good cholesterol) containing the protein ApoM (in yellow) binds to the surface of their progenitor cells, it prevents them from proliferating. Right: Mice that lack the ApoM protein on their HDL develop more severe brain inflammation in a mouse model of multiple sclerosis. This inflammation is illustrated by leakage of a red fluorescent dye from blood vessels into the brain. Image
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