Potential Target Identified to Reduce Liver Damage, Prevent Cancer

Researchers have identified a potential point of intervention that could prevent the progression of liver damage to cancer, according to a new study published in the Journal of Clinical Investigation.

A triggering receptor expressed on myeloid cells-1, also known as TREM-1, activates inflammation short-term following an insult, such as a laceration, or in response to external invaders, such as bacteria. However, for the first time, researchers have found that, when activated by chronic offending agents such as hepatitis and obesity, TREM-1 can contribute to a destructive level of inflammation that results in liver damage and possibly cancer.

According to the researchers, this transformation can occur in 5 to 50 years, and could be reversible up to the point of cirrhosis if the offending agent is stopped. The findings suggest that potentially targeting this receptor on Kupffer cells, the liver’s resident macrophages, could return TREM-1 activation to normal levels to reduce damage.

“Right now we have a treatment for hepatitis C, for example, which is very efficient, if we treat it before too much damage is done,” study author Anatolij Horuzsko, PhD, reproductive immunologist in the Georgia Cancer Center and Department of Medicine at the Medical College of Georgia at Augusta University, said in a press release. “But we don’t have treatment for alcohol- or obesity-related damage.”

To examine TREM-1 activity in the face of chronic liver disease, the researchers created a mouse model using carbon tetrachloride. They observed that TREM-1 activation increased and remained high on a larger number of Kupffer cells, as well as other immune cells circulating the body.

Deleting TREM-1 from the model reduced inflammation, injury, and subsequent fibrosis, according to the study. When returned to the mice, TREM-1 caused inflammation and related damage to rapidly increase again. Additionally, the researchers determined that TREM-1 recruits other pro-inflammatory cells from the bone marrow of the liver, which further multiplies inflammation, liver cell damage, and death.

As such, TREM-1 activity sets off a cascade of damaging effects. Damage-associated molecular patterns released when liver cells die further activate TREM-1 on the macrophages. When this happens, the macrophages activate stellate cells, leading to collagen production.

“Efficiency goes down and it causes additional damage to liver cells that already have been damaged by something like hepatitis or obesity,” Dr Horuzsko said in the press release.

TREM-1 models also showed high levels of enyzmes alanine aminotransferase and aspartate aminotransferase, both indicators of liver injury. However, without TREM-1 expression, rates went up only short-term before returning to pre-injury levels.

“TREM-1 is a molecule that can be very dangerous and is normally very controlled in the body,” Dr Horuzsko said. He noted that, in hepatitis B for example, high levels of TREM-1 expression on stellate cells is considered an indicator of poor prognosis.

“The balance in our body is very, very tightly regulated and important. Alcohol, obesity, and hepatitis viruses all change the balance,” he concluded.

Reference

New target could prevent progression of liver damage to cancer [news release]. https://jagwire.augusta.edu/archives/55991. Accessed August 29, 2018.