by Haim Moore
graphics by MacKenzie Mauger

When you get sick or injured, you will usually notice redness, heat, swelling, and pain. These symptoms are, interestingly, not the result of the pathogen or damage themselves, but rather of the reaction of your own immune system to them. These are typical manifestations of inflammation, the coordinated rush of many different immune cells to the site of injury in response to foreign invaders or damage. Sometimes, when faced with these hostile stimuli, cells induce their own necessary demise, in a process known as programmed cell death, which can aid the immune system response. 

Pyroptosis, from the Greek words for fire and falling, is one such form of programmed cell death that is triggered by infections and enhances the overall activity of the immune system by increasing inflammation. But how exactly do cells know to trigger and communicate their own destruction? In recent years, pyroptosis research has begun to answer how cells initiate their own fiery death and has opened the possibility for novel infection treatment options. In this article, we will give an overview of programmed cell death and describe how researchers are translating those raw scientific findings into potential therapeutics.  

What is cell death anyway? 

Cell death happens all the time. In fact, cell death is critical to shaping body parts during development and billions of cells in your body die every day to make room for younger, more healthy cells. But how exactly do we define death in the world of cells?   

You can consider a cell to be dead when it can no longer function normally. The two main causes of death are when cells discover an internal defect and initiate their own demise or when an external hazard damages them beyond repair. 

We call the external damage cell death scenario necrosis (Figure 1, left). Think about when a cat scratches you. The cat’s sharp nails physically rip your skin cells apart and destroy them before they have a chance to react. In this case, the inner contents of your cells spill out all over their neighbors. This can be dangerous because the spillage makes infections easier to spread, but also because the cell spillage acts as a danger signal that increases inflammation and unnecessary damage to your body. 

The self-initiated cell death after the discovery of damage, on the other hand, is typically called programmed cell death (Figure 1, right). The most common form is apoptosis, but other forms of cell destruction, like pyroptosis, which we will talk about later, can be triggered. Cells can self-destruct because, for example, they can no longer absorb nutrients effectively, or because they are infected with a pathogen, like a virus, and want to prevent its spread. The main difference between apoptosis and necrosis is how the cell dies. Once the cell decides to initiate apoptotic cell death, the cell is broken up from the inside out without ever damaging its external confining boundary (called outer membrane). As the outer membrane remains intact, the contents of the dying cell remain nicely packaged and other cells can clean them up. But other forms of programmed cell death, namely pyroptosis, are less contained.

Pyroptosis: the spark that ignites an immune system

If programmed cell death is a highway, pyroptosis would be one of the exits that a cell could take to get off the highway. Different signals will make cells take different cell death forks down the road. Pyroptosis roughly translates into “fiery death.” Remember how inflammation, the immune system’s rush to the site of infection or injury, results in redness and heat? The “fiery” part of the pyroptotic death is a hint that it involves the immune system and triggers inflammation.

Pyroptosis was first identified by looking at salmonella-infected cells, which seemed to die while rupturing. While rupturing is typically associated with necrosis, the death of these infected cells seemed to be dependent on programmed molecular pathways. So, the researchers identified a cell death that looked like uncontrolled, damage-induced death, but was in fact a programmed self-destruction! In pyroptosis, the discovery of foreign pathogens signals cells to die while also making small pores on the cell surface (Figure 2). These pores are just large enough to release small molecules called cytokines that then alert the immune cells. But pyroptosis is still more controlled than necrosis. Think about pyroptosis as a slowly leaking water balloon while necrosis is an instantaneously popping air balloon. 

The more researchers continue to look at human disease, the more pyroptosis appears to be associated with immune system activation. This connection gives us a powerful tool in designing potential therapeutics that manipulate the cellular pathway of programmed but leaky cell death to control the immune system response.

Harnessing pyroptosis for patient therapies 

Even though the field of pyroptosis is new, there are already promising applications of the basic research into pharmaceutical applications. One recent study at the Harvard Medical School found that Disulfiram, a drug approved by the Food and Drug Administration (FDA) to treat alcoholism, can stop pyroptosis by blocking the formation of the leaky pores on the cell surface. As pyroptosis is associated with higher levels of inflammation, human diseases characterized by excessive inflammation could benefit from therapeutics that can prevent or moderate pyroptosis. Thus, the discovery of this novel mechanism of action of Disulfiram opens the promising possibility that we can repurpose the drug in inflammatory disease. We can imagine that in a disease where inflammation is lower than it should be, we can harness pyroptosis to activate and target the immune system where it is supposed to go. In diseases where inflammation is higher than it should be, on the other hand, we can attempt to temper inflammation by limiting or stopping pyroptosis (Figure 3).

Learn to code to control the program 

Programmed cell death research is young. New aspects of these cell death pathways, like apoptosis and pyroptosis, are still being explored and the field is growing at a rapid pace. Pyroptosis and its therapeutic possibilities have set both academia and the biotech industry ablaze with the task of translating raw scientific findings, like how pyroptosis is associated with holes in the cell surface, to potential therapeutic options for controlling inflammation in patients. Even aging, a process by which inflammation becomes more chronic, could potentially be slowed with pyroptotic-targeting pharmaceutical agents.

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Haim Moore is a first-year MMSc student in the Immunology program at Harvard Medical School, where he is studying the role of innate T cells in the tumor microenvironment. You can find him on Instagram as @haimmoore.

MacKenzie Mauger is a second-year Ph.D. student in the Biological and Biomedical Sciences program at Harvard Medical School, where she is studying the role of condensate formation in epigenetic memory. You can find her on Twitter as @MacKenzieMauger.

Cover Image: “Human macrophage rupturing after infection with Chlamydia” is licensed with CC BY-NC 4.0. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc/4.0/

For More Information:

• Read this article to learn more about six different types of cell death in an easily digestible way.
• If you’re interested in the biology of inflammatory cell death, this video describes the molecular pathways of apoptosis and necrosis in detail.