NEWS OF THE WEEK
AUTOIMMUNE DISEASE: Two metabolism inhibitors reverse disease symptoms in lupus mice
I
N A PATIENT with the autoimmune disease lupus,
immune cells attack the body’s own tissues as if they were an invading pathogen. This can lead to damage to the skin, joints, kidneys, and even the brain. Now a team of immunologists reports that some of these errant immune cells have an overactive metabolism, and that inhibiting two key metabolic pathways can reverse lupus symptoms in mice (Sci. Transl. Med. 2015, DOI: 10.1126/scitranslmed.aaa0835). The study provides compelling evidence that a combination of metabolic inhibitors could be an effective lupus therapy, say Manan M. Mehta and Navdeep S. Chandel of Northwestern University in a perspective they wrote about the study. Before testing these inhibitors, Laurence M. Morel at the University of Florida and her colleagues first studied the metabolism of CD4+ T cells. In lupus, the immune cells command B cells to pro-
SUNLIGHT IMPLICATED IN DARK CHEMISTRY SKIN CANCER: UV light helps damage
DNA hours after exposure
T
HE SUN CAN induce cancerous DNA dam-
age in skin cells even after it sets, according to a new study (Science 2015, DOI: 10.1126/ science.1256022). An international team of scientists has found that radical species generated by ultraviolet light can cause damage to DNA long after irradiation stops. They do this with the aid of compounds derived from melanin, a pigment known to shield mammals from burns and other harmful UV effects. The melanin-assisted process creates lesions known as cyclobutane pyrimidine dimers in DNA, which can lead to mutations that cause melanoma, a type of skin cancer. These lesions are identical to the well-known genetic alterations caused when UV light directly strikes DNA. “But at least half of the dimers you get come in the dark, rather than during your trip to the beach,” says Douglas E. Brash of Yale University, who led the new study.
duce autoantibodies, which target the body’s own tissue. When T cells are on the hunt for pathogens, they ramp up their metabolism so they can proliferate quickly. Morel hypothesized that in lupus patients, overly aggressive T cells would also have an overly active metabolism. To test the idea, the researchers looked at two pathways involved in glucose metabolism: glycolysis and oxidation that occurs in a cell’s energy-generating mitochondria. Compared with T cells OH from healthy mice, lupus cells had elevated pH levels and consumed O HO more oxygen, signs of high rates HO of glycolysis and mitochondrial OH oxidation, respectively. 2-Deoxyglucose Morel and her team then tested two metabolic inhibitors on lupus mice: 2-deoxyglucose, which inhibits glucose metabolism, and metformin, which slows electron transport in the oxidation pathway in mitochondria. Lupus mice that received the two compounds in their drinking water showed a reversal of symptoms over three months. Levels of autoantibodies dropped, kidney health improved, and T-cell activation returned to normal. Metformin is already approved by the Food & Drug Administration for treating type 2 diabetes, but Morel says she needs to collect more data on the inhibitors and their effects on the immune system before starting a clinical trial in lupus patients.—MICHAEL TORRICE
These chemically mediated lesions can take hours to evolve, Brash explains, whereas direct DNA damage occurs within picoseconds of exposure. Using techniques including mass spectrometry and highperformance liquid chromatography, the researchers identified a previously unrecognized process that could play a significant role in melanomas. UV light stimulates enzymes that produce superoxide and nitric oxide, Brash says. These radicals react to create peroxynitrite, which can oxidize and fragment melanin polymers. Peroxynitrite further reacts with these fragments, creating unstable compounds. These molecules degrade into electrically excited species able to dump their energy into DNA and damage it. “There’s no other way to explain how you get the damage after you turn the light off,” says John-Stephen Taylor, a chemist at the University of Washington in St. Louis, who was not involved in the study. In a written perspective, Taylor calls the new report a “brilliant piece of detective work” (Science 2015, DOI: 10.1126/science.aaa6578). The researchers hope their work will help create topical treatments or “evening after” sunscreens to block this chemical damage, Brash says. In the meantime, people can protect themselves by wearing sunscreen and staying out of tanning beds. “Basically, don’t fry yourself,” he suggests.—MATT
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NATIONAL CANCER INSTITUTE
ONE-TWO PUNCH FOR LUPUS
DAVENPORT
CEN.ACS.ORG
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FEBRUARY 23, 2015
Melanomas, such as this one, are often caused by exposure to UV light.
