Balancing Immune Health and Chronic Inflammation: A Delicate Trade-off

Having an adequately functioning immune system for extended lifespans might come with the trade-off of chronic inflammation. Some immune cells are programmed to undergo inflammatory deaths to protect against infections, but this can also happen randomly when no pathogens are present.

Our innate immune system comprises cell groups that react swiftly to invasive pathogens such as viruses and bacteria. These cells typically detect microorganisms when they invade or infect them.

“With minimal information such as molecules of viral DNA, immune cells can swiftly decide on a course of action, often opting for self-destruction,” says Randal Halfman from the University of Kansas Cancer Center.

This type of cell death, known as pyroptosis, is triggered by a double death domain protein. These proteins usually float within innate immune cells, but upon encountering pathogens, they assemble into crystal-like structures. This action activates another protein that kills the cells by creating holes, leading to ruptures and releasing inflammatory signals that assist the immune system in pathogen clearance.

To delve deeper into this process, Halfman and his team carried out various laboratory experiments investigating human death-fold domain proteins in yeast cells. This process allowed them to identify five types of these proteins with chemical characteristics that predispose them to naturally form crystal-like structures in the absence of pathogens. They then analyzed existing data to assess the levels of these proteins in uninfected human immune cells.

From this analysis, we determined that certain innate immune cells, such as macrophages that engulf and eliminate pathogens, possess five times more death-fold domain proteins at concentrations sufficient to spontaneously assemble and trigger cell death. “At high enough concentrates, these particles are more likely to randomly conform into crystal structures during the cell’s lifespan,” Halfman explains.

Such phenomena can accumulate with age, contributing to chronic inflammation associated with various conditions, including cancer and Alzheimer’s disease, according to Halfman. “It seems we’ve evolved this way to fend off infections, but it may also lead to chronic inflammation,” he asserts.

This pathway provides protection against infections from birth and enhances our likelihood of aging, though it might also predispose us to inflammation-related diseases later in life, Halfman notes. “If these persistent irritations continue over time, the resulting inflammatory damage can accumulate,” he elaborates. Andy Clark from the University of Birmingham, UK, agrees.

The development of medications that prevent spontaneous cell death could potentially alleviate chronic inflammation related to aging, Halfman suggests. However, Clark cautions that this might render individuals more vulnerable to infections.