Good immune health may come at the expense of chronic inflammation

Having a strong immune system that supports longevity may inadvertently lead to chronic inflammation. Certain immune cells partake in a form of inflammatory cell death designed to combat infections, yet this can also occur without any pathogens present. Such random cell deaths contribute to ongoing inflammation linked to numerous health issues.

The innate immune system comprises cells that swiftly react to infectious invaders like bacteria and viruses. These cells typically identify pathogens by capturing fragments of them or through infections.

“Drawing from minimal information, like a single molecule of viral DNA, immune cells have only moments to make critical decisions, often opting for altruistic suicide to amplify inflammatory signals,” states Randal Halfmann from the Stowers Institute for Medical Research in Kansas City, Missouri.

Researchers were already aware that this particular form of cell death, known as pyroptosis, is triggered by specific death-fold domain proteins. While these proteins typically float in innate immune cells, they form crystalline structures upon interacting with a pathogen, which subsequently activates another protein to rupture the cell, releasing inflammatory signals essential for pathogen clearance.

To investigate this mechanism, Halfmann and his team conducted laboratory experiments studying human death-fold domain proteins in yeast cells. This research led to the discovery of five types of these proteins with properties that predispose them to form crystal-like structures even in the absence of pathogens. The researchers analyzed existing data to assess the presence of these proteins in uninfected human immune cells.

From their findings, it was determined that some innate immune cells, particularly macrophages—responsible for engulfing and destroying invaders—harbor these five death-fold domain proteins at concentrations high enough to potentially trigger unintended cell death. “When present in significant amounts, the likelihood of these proteins forming crystalline structures increases over the lifespan of a cell,” explains Halfmann.

Such occurrences may lead to chronic inflammation, which intensifies with age and has been associated with diseases like cancer and Alzheimer’s disease. “The evolutionary advantage we gained in combating infections could come with the consequence of chronic inflammation later in life,” Halfmann adds.

This mechanism equips our bodies to combat infections from birth, providing a better chance of survival into old age, yet it also raises the risk of inflammation-related diseases as we age. “If these sporadic inflammatory responses occur throughout a person’s life, the resultant damage accumulates over time,” claims Andy Clark from the University of Birmingham, UK.

There is potential for developing medications aimed at preventing these spontaneous inflammatory cell deaths to reduce age-related inflammation, notes Halfmann. However, Clark emphasizes that this could render individuals more vulnerable to infections, and thus the benefits might not outweigh the risks.