24 March 2008

Pyroptosis: to die, so with music!

The cells are equipped with several self-destruct programs. Most cells die quietly, with the help of apoptosis (from the Greek "leaf fall"). A recent paper by Harvard scientists (Michael Overholtzer et al., A Nonapoptotic Cell Death Process, Entosis, that Occurs by Cell-in-Cell Invasion // Cell, Vol 131, 966-979, November 30, 2007) describes another mechanism of programmed cell death, which the authors called entosis, by analogy with endocytosis: a cell that has come to say goodbye to life, at the same time climbs inside a neighboring, healthy cell and "forces" it to digest itself. Necrosis – unplanned cell death as a result of chemical or physical exposure – leads to the destruction of cell membranes, the ingress of the contents of dying cells into the extracellular space and inflammation as a protective reaction that stimulates the immune system to destroy the decay products of dead cells.

Scientists at the University of Washington, working under the leadership of Dr. Brad T. Cookson, have discovered another mechanism of cellular self–destruction characteristic of potentially dangerous cells - for example, dying under the influence of infectious agents. Such cells report their death to the whole body, releasing chemical signals that cause the development of inflammation, which helps the body fight infection, but can sometimes damage healthy tissues. The authors called this mechanism of cell death pyroptosis – "death by fire".

The intracellular enzyme caspase-1 plays a critical role both in inflammation that is dangerous for the body and in resistance to infections. It is responsible not only for cell death, but also for the synthesis of pro-inflammatory proteins released during this process. Mice lacking this enzyme are susceptible to infections, but resistant to toxic shock, tissue damage due to lack of oxygen and inflammatory bowel disease.

Схематичное изображение механизма клеточной гибели, получившего название пироптозSchematic representation of the mechanism of cell death, called pyroptosis.
A toxin or an infectious agent activates the enzyme caspase-1, which triggers several processes inside the cell, some of which lead to the destruction of DNA, some to the release of cytokines acting as chemical alarms, and some to the formation of tiny pores in the membrane through which water enters the cell. As a result, the cell swells, bursts and throws its contents into the extracellular space.

Cookson Laboratory researchers have been studying caspase-1 and its involvement in the mechanism of proinflammatory programmed cell death for a long time. In their latest work, they studied the triggering of this mechanism under the action of two different agents: anthrax toxin and salmonella.

It turned out that these agents activate caspase-1 through different mechanisms, but in both cases the end result is the same process of cell death, consisting in DNA cleavage, activation of inflammatory cytokines and release of cellular contents into the extracellular space.

According to Cookson, this discovery will help develop research models to study important mechanisms of pro-inflammatory programmed cell death. In addition, the discovery confirms the assumption that different pathogens trigger different mechanisms leading to cell death.

The study of this system will shed light on the mechanisms of both beneficial and harmful cell death for the body, as well as on the strategies used by infectious agents to manipulate the body's reactions. As part of earlier work on the study of yersinia, the causative agent of the plague, the authors demonstrated that the process of cell death can be redirected from a passive non–inflammatory mechanism to a more effective inflammatory one in the fight against the causative agent. This discovery indicates the possibility of treating diseases by modulating the processes of cell death.

In addition to the protective function performed by caspase-1 in the fight against infections, this enzyme also plays a role in the processes developing in many diseases characterized by inflammatory processes that damage the tissues of the heart, brain, lungs, nerves and kidneys. The authors believe that understanding the mechanisms of cell death will help in the development of new treatments for fatal or disability-reducing diseases, such as serious infections, stroke, heart attack and cancer.

Portal "Eternal youth" www.vechnayamolodost.ru based on the materials of the University of Washington


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