What’s the Difference Between Apoptosis, Necroptosis, and Pyroptosis?

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The word “death” often brings up negative feelings and is associated with harm. Within the human body, however, cell death happens every second and the processes that regulate cell death are often beneficial and necessary to preventing infections, cancer, and other abnormalities. Apoptosis, necroptosis, and pyroptosis are all methods of programmed cell death, regulated by genes and signal molecules within the cell. These forms of cell death have distinct attributes that can help or hurt the body.

Apoptosis was the first type of programmed cell death to be discovered, and it is often referred to as “cell suicide”. Apoptosis occurs due to an activation of instructions within cell DNA. Apoptosis is commonly activated through an intrinsic pathway, which starts when signal molecules within the cell detect abnormal cell growth or damage in cellular DNA. The signal molecules activate genes within the cell that cause the cell to commit apoptosis. An important example of the intrinsic pathway is within cell division. The p53 protein is an example of a tumor suppressor, which causes cells to commit apoptosis when it detects that cells are dividing too quickly. This prevents tumors and abnormal cell growth. When signal molecules activate genes within the cell, the cell releases proteases, which are enzymes that break bonds between proteins. These proteases cause the cell membrane to disintegrate and causes DNA to condense and break up into fragments. The material inside the cell is released in small membrane-bound capsules called apoptotic bodies. Then cells called phagocytes engulf and dispose of these apoptotic bodies, acting as the cleanup crew for the dead cell. Although apoptosis is necessary for preventing cancer and regulating cell growth, too much apoptosis can lead to serious diseases such as Parkinson’s disease and Alzheimer’s disease.

Necroptosis is a type of regulated cell death triggered by outside trauma or deprivation, compared to apoptosis which can start from signals within the cell. Necroptosis is a regulated form of necrosis, which is uncontrolled cell death due to factors outside the cell. The most common way that necroptosis takes place is through the activation of the RIPK3 gene in human cells. When a signal from outside the cell binds to a receptor on the cell membrane, the RIPK3 gene is activated and causes a chain reaction inside the cell. This chain reaction leads to lysis of the cell, which is when the cell membrane bursts and the contents of the cell spill out. Unlike apoptosis, after the cell bursts, phagocytes do not engulf the dead cell material and it is not removed from cell circulation. Therefore, the remnants of the dead cell often trigger reactions with nearby cells and activate the immune system. The bursting of cells that happens during necroptosis is used to fight infection and combat viruses through the release of substances called DAMPs, which stands for Damage-Associated Molecular Patterns. DAMPs alert surrounding cells of danger and promote inflammation, which is how the body fights injuries and infections. When the signals triggering necroptosis malfunction and necroptosis happens too often, it can contribute to inflammatory diseases such as psoriasis, ulcerative colitis, and Crohn’s disease.

Pyroptosis is the primary response of the cell to infectious organisms and is triggered by the immune system. The main difference between pyroptosis and necroptosis is how it is activated: while the RIPK3 gene commonly activates necroptosis, pyroptosis is activated by the enzyme caspase-1. For this reason, pyroptosis is also called caspase-1 dependent cell death. Caspase-1 activates proteins that prompt an immune response from the cell. This response causes the same lysis seen in necroptosis where the cell membrane bursts and the contents of the cell spill out. The release of DAMPs from the ruptured cell triggers inflammation and a larger immune response from surrounding cells and organs. Pyroptosis causes more inflammation than necroptosis and is often dangerous to the body. Pyroptosis triggered by pathogens often contributes to symptoms of infectious disease because of the release of DAMPs and inflammatory molecules. Because of the strength of pyroptosis, this form of programmed cell death is used with apoptosis to kill cancerous cells. However, because pyroptosis causes inflammation, it can also make the environments around cells more suitable for tumors to grow.

Apoptosis, necroptosis, and pyroptosis are all forms of programmed cell death that activate genes and molecules inside the cell. These different types of cell death promote inflammation, respond to pathogens, and suppress cancer. Programmed cell death is an important field of study because if scientists can find a way to control cell death, they can trigger responses to tumors, injuries, and disease. Cell death is a necessary part of human life, and these three forms are constantly being studied to understand how they operate and how scientists can harness them to create better treatments for the future.

— Remi Shendell