“Explosive” cell death gene variant carried by millions of people
Researchers have found that millions worldwide carry a gene variant that controls ‘explosive’ cell death linked to inflammation. They say it may explain why some people are prone to developing inflammatory diseases and potentially lead to the development of personalized treatments.
Cell death is how the body rids itself of damaged, unwanted, or diseased cells. One form of cell death, apoptosis, is considered ‘programmed’ because it’s a highly regulated process. Necrosis, conversely, is ‘unprogrammed’ due to its uncontrolled nature. Then there’s a novel form of cell death called necroptosis, mimicking both apoptosis and necrosis.
Necroptosis is distinguished from other forms of cell death by its ferocity: essentially, the cells explode, setting off an alarm that other cells in the body respond to. Whereas apoptosis usually causes an immunologically silent response, necroptotic cell death, which is gatekept by the MLKL gene, releases molecules that promote inflammation and can lead to disease.
A new study led by researchers at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, has examined how necroptotic cell death is affected when the gene that controls it is altered.
“This is a good thing in the case of a viral infection, where necroptosis not only kills the infected cells but instructs the immune system to respond, clean things up, and start a more specific, long-lived immune response,” said Sarah Garnish, the study’s lead author. “But when necroptosis is uncontrolled or excessive, the inflammatory response can actually trigger disease.”
The researchers found that some people are born with polymorphism – the presence of two or more variant forms of a specific DNA sequence – at MLKL amino acid 132 (S132P), which enhances the ability of MLKL to kill cells.
“For most of us, MLKL will stop when the body tells it to stop, but 2-3% of people have a form of MLKL that is less responsive to stop signals,” Garnish said. “While 2-3% doesn’t seem like much, when you consider the global population, this adds up to many millions of people carrying a copy of this gene variant.”
To examine the potential human-disease-causing effects of this MLKL variant, the researchers introduced the mouse version of it into genetically modified mice and found that it conferred a gain-of-function effect that resulted in immune cell defects and dysfunctional blood cell formation (hematopoiesis).
The researchers also observed a reduction in the number of inflammatory monocytes, cells that selectively travel to the sites of inflammation, produce inflammatory cytokines, and contribute to local and systemic inflammation. This was the case in mice with induced peritonitis (inflammation of the peritoneum, the membranes of the abdominal wall and organs) and those infected with Salmonella bacteria.
The researchers say the importance of their findings lies in how this kind of genetic variation interacts with factors such as lifestyle, history of infections, and broader genetic makeup to increase the risk of inflammatory diseases. This is known as polygenic risk, the combined influence of multiple genes on developing a certain trait or condition.
“Taking type 2 diabetes as an example, it’s rare that just one gene change determines whether someone will develop the condition,” said Joanne Hildebrand, the study’s corresponding author. “Instead, many different genes play a role, as do environmental factors, like diet and smoking.”
They say that MLKL S132P polymorphism may be key to understanding how MLKL and necroptosis modulate the progression of polygenic human diseases.
“We haven’t tagged this MLKL gene variant to any one particular disease yet, but we see real potential for it to combine with other gene variants and other environmental cues to influence the intensity of our inflammatory response,” Hildebrand said.
Their findings also raise the possibility of developing a personalized drug treatment targeting MLKL. But, for now, the researchers are investigating whether uncontrolled necroptosis could be beneficial in some circumstances, such as providing an improved defensive response to certain viral infections.
“Gene changes like this don’t usually accumulate in the population over time unless there is a good reason for it – generally, they get passed on because they do something good,” said Garnish. “We’re looking at the downside of having this gene change, but we’re looking for the upsides as well.”
The study was published in the journal Nature Communications.