Organ ‘Crosstalk’ Extends Harms of Inflammation from Liver to Brain

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OKLAHOMA CITY – As people age, the liver is among several organs that experience chronic, low-grade inflammation, a state that keeps the immune system activated even though there is no threat.

Liver inflammation has been linked to several liver diseases, such as fatty liver disease and liver cancer, but the liver also communicates with the brain, triggering inflammation that can lead to cognitive decline. University of Oklahoma researcher Deepa Sathyaseelan, Ph.D., recently earned a $2 million grant from the National Institutes of Health to study the reasons behind this liver-brain crosstalk and test methods of protecting both organs.

Specifically, Sathyaseelan is studying necroptosis, which is a natural form of cell death with a downside: Cells that die through necroptosis burst and release substances that lead to inflammation. In previously published research involving an aging mouse model, Sathyaseelan and her team demonstrated the damaging effects of necroptosis in the liver, as well as the reduction of those effects when necroptosis was blocked. They also found that activating necroptosis in the liver increased liver inflammation and, surprisingly, increased brain inflammation, which affected the mice’s ability to build nests, a possible sign of cognitive impairment.

On the strength of those studies, she earned this new NIH grant to better understand how necroptosis of liver cells causes the inflammation that affects both the liver and the brain with age. Such knowledge is crucial for ultimately devising a way to reduce inflammation and improve tissue function.

“We hypothesize that when liver necroptosis is activated, the liver secretes toxic or inflammatory molecules that enter the bloodstream and cross the blood-brain barrier, where they cause inflammation in the brain,” she said. “This type of organ crosstalk is becoming very important in research. Usually, when we study a disease condition, we focus on one organ, but when we do that, we miss the systemic effect.

“This study tells us that, with age-associated cognitive decline or Alzheimer’s disease, we shouldn’t think only about targeting the brain. We also need to think about how liver inflammation plays a role,” said Sathyaseelan, an assistant professor of biochemistry and physiology at the OU College of Medicine. She is also a research member of OU Health Stephenson Cancer Center and a researcher in the Center for Geroscience and Healthy Brain Aging.

Sathyaseelan will investigate several additional inflammation-related factors in her study. Macrophages are immune cells that function positively during infections or injuries by “eating” dead cells, thereby boosting the body’s ability to heal. However, when chronic inflammation puts the body in a constant state of alert, macrophage behavior becomes strange and further contributes to inflammation.

She will also delve into the role of cellular senescence in liver inflammation. Senescent cells are essentially in limbo – they are no longer replicating, but neither do they die off. Senescence can be positive if, for example, it stops the cell’s transformation into a cancer cell. But senescent cells also increase inflammation. Sathyaseelan will study the role of necroptosis on both macrophages and cellular senescence and will seek to reduce inflammation using compounds known to inhibit necroptosis.

Her findings may have wide-ranging implications for both liver disease and cognitive impairment in the aging process. Few treatments are available for conditions like fatty liver disease and liver cancer, and older adults often are not candidates for liver transplants. In the brain, the longer that increased inflammation persists, the higher the likelihood that mild cognitive impairment will turn into severe cognitive dysfunction. Complicating the outlook for both conditions is the prevalence of obesity, another significant cause of inflammation in the body.

“What we have found in our mice studies so far matches what is reported for patients – that people with liver diseases have high inflammation in the liver and also have cognitive issues,” Sathyaseelan said. “Our key question is what is causing this increase in inflammation in aging? It is important that we advance our knowledge in this area because it is critical that we develop new ways to treat these diseases.”