Researchers have discovered that millions of people around the world carry a genetic variant that controls "explosive" cell death linked to inflammation. They say this may explain why some people are susceptible to inflammatory diseases and could lead to the development of personalized treatments. Cell death is the body's way of getting rid of damaged, unwanted, or diseased cells.
Apoptosis is a form of cell death that is considered "programmed" because it is a highly controlled process. Instead, it is considered "unprogrammed" due to its uncontrolled nature. There is also a new form of cell death called necrosis, which mimics both apoptosis and necrosis.
What distinguishes necrosis from other forms of cell death is its ferocity: essentially, a cellular explosion that sets off an alarm that causes other cells in the body to react. Apoptosis typically triggers an immune-silencing response, whereas necroptotic cell death, gated by the MLKL gene, releases molecules that promote inflammation and may lead to disease.
A new study led by researchers at the Walter Eliza Hall Institute (WEHI) in Melbourne, Australia, examined how necrotic cell death is affected when the genes that control it are altered.
"This is a good thing in the case of a viral infection," said Sarah Garnish, the study's first author. "Not only do necrotic cells kill infected cells, they also instruct the immune system to respond, clear the virus, and initiate a more specific, longer-lasting immune response." But when necrotic cells increase out of control or become excessive, the inflammatory response can actually trigger disease. "
Researchers found that some people are born with a polymorphism - the presence of two or more variant forms of a specific DNA sequence - MLKL amino acid number 132 (S132P), which enhances MLKL's ability to kill cells.
"For most of us, MLKL stops when the body tells it to stop, but there are 2 to 3 percent of people whose MLKL is less responsive to the stop signal," Garnish said. "While 2 to 3 percent of people doesn't seem like a lot, when you consider the global population, it means there are millions of people carrying copies of this genetic variant."
To study the potential pathogenic effects of this MLKL variant in humans, the researchers introduced the mouse version of the MLKL variant into genetically modified mice and found that this variant produced a gain-of-function effect, leading to immune cell defects and dysfunction of blood cell formation (hematopoiesis).
The researchers also observed a reduction in the number of inflammatory monocytes, cells that selectively travel to sites of inflammation, produce inflammatory cytokines, and contribute to local and systemic inflammation. This condition occurred in mice with induced peritonitis (inflammation of the peritoneum, abdominal wall membranes and organs) and in mice infected with Salmonella.
The researchers say the importance of their findings lies in how this genetic variant interacts with factors such as lifestyle, infection history and broader genetic makeup to increase the risk of inflammatory diseases. This is called polygenic risk, the combined effect of multiple genes on a trait or disease.
Joanne Hildebrand, corresponding author of the study, said: "In the case of type 2 diabetes, it is rare that a change in one gene determines whether a person will develop the disease. Instead, many different genes play a role, as do environmental factors such as diet and smoking."
They say the MLKLS132P polymorphism may hold the key to understanding how MLKL and necrosis regulate the progression of the multigenic human disease.
"We haven't linked this MLKL gene variant to any one specific disease, but we see real potential for it to combine with other genetic variants and other environmental cues to influence the strength of our inflammatory response," Hildebrand said.
Their findings also offer the possibility of developing personalized drug treatments for MLKL. But for now, researchers are studying whether uncontrolled necrosis can be beneficial in certain circumstances, such as providing a better defense response against certain viral infections.
Genetic changes like this don't usually accumulate in a population over time unless there's a good reason - generally, they're passed on because they've done something good. Researchers are focusing on the downsides of this genetic change, but are also looking for its benefits.
The research was published in the journal Nature Communications.