Pyroptosis

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The Pyroptose is a highly flammable death program , activate the vertebrate cells infected with intracellular pathogens (eg. As viruses or bacteria ) are infected to prevent spread of infection. The name was coined in 2001 and means death by fire or fever.

function

Pyroptosis is supposed to prevent the spread of an intracellular infection. The classic example are macrophages that  are infested with Salmonella typhimuroum ,  Shigella flexneri , Listeria, Legionella or other bacteria that live in their cytoplasm. Cells of the intestinal mucosa that are infected with Salmonella also die from pyroptosis and release the bacteria back into the intestinal lumen. In this way, they prevent the salmonella from penetrating deeper into the tissue through the intestinal mucous membrane barrier.

mechanism

Cell death is mediated by inflammasomes . These protein complexes typically consist of sensors or receptors for bacterial molecules and other cell stress signals, the enzyme caspase-1 and adapter proteins. The accumulation of these components in the inflammasome activates caspase-1. The enzyme then probably cuts up proteins that are involved in glycolysis . This prevents the production of the energy carrier ATP , which both the pathogens and the host cell need.

Caspase-1 also cuts the preforms of the cytokines IL-1β and IL-18 so that they are activated and excreted. They trigger local inflammation and attract immune cells, especially neutrophils . These fight the bacteria that are expelled or escaped from the infected cells. Neutrophils themselves, unlike macrophages, cannot undergo pyroptosis. The simultaneous release of cytokines, bacteria, antimicrobial substances and danger-associated molecular patterns (DAMPs) leads to a strong inflammatory reaction .

Parallels and differences to apoptosis

As in intrinsic apoptosis , enzymes from the caspase family are involved in pyroptosis : pathogen-associated molecular patterns (PAMPs) in pyroptosis and the mitochondrial protein cytochrome C in apoptosis release the assembly of Caspase-containing protein complexes (inflammasomes or apoptosomes), which carry out the later steps of programmed cell death. The similarity of the mechanisms of action is attributed to the structural similarity and relationship between bacteria and mitochondria: The mitochondria, the destruction of which is a central step in intrinsic apoptosis, evolved from intracellular bacteria.

In contrast to the largely silent, i.e. non-inflammatory apoptosis, pores develop in the outer membrane of the cells in pyroptosis, which then swell due to the osmotic pressure and finally burst ( lysis ). In this respect, pyroptosis is more like necrosis .

Pathological effects

Excessive pyroptotic macrophage death can weaken the immune system, which then lacks professional phagocytes and antigen-presenting cells .

In the course of an HIV infection , infected dormant T lymphocytes die due to pyroptosis without the retroviruses being completely eliminated: They give way to other T lymphocytes, which then die due to apoptosis. The lack of T helper cells eventually leads to AIDS.

If large amounts of dangerous signals or DAMPs escape from numerous pyroptotic cells at the same time, this can lead to sepsis and a cytokine storm : A mass release of cytokines attracts numerous immune cells, which in turn release further cytokines, etc.

Pyroptosis can also be involved in autoimmune diseases if the lysis of the cells releases autoantigens that trigger or intensify attacks by autoreactive immune cells. However, pathogens have only been identified as triggers in a few autoimmune diseases. Presumably, the cells of people with a corresponding genetic predisposition can go through pyroptosis even without such a trigger.

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