Problems like obesity and alcoholism appear to chronically trigger in the liver a receptor known to amplify inflammation in response to invaders like bacteria, scientists report.

The relentless, increased activity of TREM-1, in turn, accelerates injury and scarring of the liver, the first step toward cirrhosis and liver cancer, says Dr. Anatolij Horuzsko, a reproductive immunologist in the Georgia Cancer Center and Department of Medicine at the Medical College of Georgia at Augusta University.

TREM-1, or triggering receptor expressed on myeloid cells-1, is known to help turn up inflammation short-term to help us deal with external invaders. It has increased activity immediately after an injury as well, when increased inflammation, damage cleanup, and collagen production aid healing.

But Georgia Cancer Center scientists report in the Journal of Clinical Investigation the first evidence that when activated by chronic offending agents, like obesity and hepatitis, TREM-1 instead contributes to a destructive level of inflammation that results in liver damage and possibly cancer.

The unhealthy transformation can occur in five to 50 years, depending on factors like the level of insult, and may be largely reversible up to the point of cirrhosis, if the offending agent is stopped, and the liver's natural ability to regenerate takes over.

Kupffer cells

Horuzsko and his colleagues think TREM-1 could one day be another point of intervention, possibly with a drug that could return TREM-1 activation to normal levels on resident, garbage-eating, watchdog immune cells called Kupffer cells.

"Right now we have treatment for hepatitis C, for example, which is very efficient, if we treat it before too much damage is done. But we do not have treatment for alcohol- or obesity-related damage," Horuzsko said.

They already are doing experiments with a drug that, because of its structure, should enable tamping down of TREM-1, but long-term goals include a drug that would target this receptor on Kupffer cells

To look at what happens in the face of a chronic problem, the scientists created a model of chronic liver disease like obesity or high alcohol consumption might, using carbon tetrachloride, a poisonous solvent found in oils, varnishes, and resin. They found TREM-1 activation went up and stayed up on a larger number of Kupffer cells in the liver as well as other immune cells circulating in the body.

When they deleted TREM-1 from the model, it reduced inflammation, injury, and subsequent fibrosis. When they gave TREM-1 back to the mice, inflammation and related damage came back with a vengeance, leading them to dub TREM-1 the main target that drives fibrogenesis.

They found TREM-1 even recruits other pro-inflammatory cells from the bone marrow to the liver, many of which could become macrophages as well, which further multiplies the inflammation, liver cell damage, and death.