Inflammation From Cellular Garbage Strike

Mutant mice that can't stop scratching themselves have led scientists to a gene--whimsically dubbed Itch--that helps control inflammation. The discovery, reported in next month's Nature Genetics, offers a surprising glimpse into the causes of inflammation and may eventually lead to new treatments for autoimmune disorders.

The discovery was accidental, says geneticist Neal Copeland of the National Cancer Institute Frederick Cancer Research and Development Center in Frederick, Maryland. While breeding experimental mice, Copeland noticed that after a few generations, mice in one strain started scratching themselves uncontrollably--to the point of ripping out their fur. Copeland's team also noted that these mice suffered from a host of immune-related problems, the most crippling being a flood of macrophages--a type of white blood cell--damaging the lungs and other organs. Macrophages are messy immune fighters, sometimes spilling out noxious chemicals that can damage cellular bystanders.

While studying an unrelated gene, Copeland's group happened upon a mutation in a nearby stretch of DNA, the previously unidentified Itch gene. Scanning a genetic database, the researchers matched the faulty gene's sequence to that of a previously defined family of genes. These genes encode enzymes called E3 ubiquitin protein ligases, which help tag a cell's worn-out or surplus proteins for destruction. Such enzymes bring together a marker protein, called ubiquitin, with the unwanted proteins. Other cellular enzymes shepherd the dross to the cell's disposal machinery, called proteasomes. Because all the itchy mice had a defective version of the E3 ligase, Copeland suspects that their ubiquitin systems fail to tag immune-related defense proteins or foreign substances called antigens for disposal--both of which then might pile up and attract too many helper macrophages to the scene, wreaking havoc with the immune response.

"There's no question that this is a very important finding," says Fred Goldberg, a cell biologist at Harvard. He predicts that the discovery will help researchers develop very specific anti-inflammatory drugs that can subtly tweak the body's immune responses by targeting distinct ubiquitin ligases and similar enzymes involved in cellular garbage disposal.