Behind pyroptotic cell death A pro-inflammatory form of programmed cell death, pyroptosis causes cells to expand and eventually burst, releasing content that then causes inflammation. We spoke to Professor Petr Broz about the work of the InflamCellDeath project in investigating the basis of pyroptotic cell death and its wider impact. A form of
programmed cell death first reported around 20 years ago, pyroptosis differs significantly from the more wellknown process of apoptosis. While apoptosis is a non-inflammatory, immunologically silent form of cell death, pyroptosis is proinflammatory. “A pyroptotic cell enlarges and balloons until it explodes. This releases cytokines and so-called danger signals that cause inflammation in the tissue,” explains Professor Petr Broz. As the Principal Investigator of the InflamCellDeath project, Professor Broz is analysing the underlying basis of pyroptotic cell death. “We know that pyroptosis is caused by a type of protein called gasdermin D, which is a pore-forming protein,” he outlines. “This protein is activated by proteolytic cleavage, by proteases. It’s believed that the N terminal part of the protein is cleaved from the C-terminal part, which is the regulatory, inhibitory domain.”
Membrane pores The N-terminus then targets the plasma membrane, where it forms huge pores. These pores allow the uncontrolled influx of water into the cell, which eventually leads to the death of the cell. “This influx of water results in the swelling and rupture of the cell, and eventually the release of inflammatory content,” says Professor Broz.
This form of programmed cell death normally occurs during infection. “Pyroptosis is the outcome of a signalling cascade known as the inflammasome pathway. A pattern recognition receptor recognises pathogenderived molecules, and assembles a signalling platform known as the inflammasome,” explains Professor Broz. “A protein called caspase 1 activates gasdermin D to kill off the cell, so that the pathogen can’t replicate anymore. It will also cause inflammation, so that other immune cells converge on the site of infection.”
says there is a lot of interest in the idea from the pharmaceutical sector. “Could we develop an inhibitor that would prevent the pore from forming and prevent the inflammation?” he asks. “This is a very interesting area for pharmaceutical companies.” There is a lot of interest in particular in the NLRP3 inflammasome, which is an important component of the innate immune system. Activation of the NLRP3 inflammasome is associated with several inflammatory disorders, and gasdermin D has been identified as an important target for therapeutic
A pyroptotic cell enlarges and balloons until it explodes. This releases cytokines that cause inflammation in the tissue. This can be very beneficial in terms of clearing a pathogen, yet an excessive inflammatory response in itself can damage healthy tissue. In some cases the inflammasome complex assembles even without an infection, due for example to a certain mutation, which may then be a factor in the development of auto-inflammatory disease. “Where the inflammasome pathway activates, you get caspase 1 activation and inflammation,” outlines Professor Broz. Blocking the gasdermin D protein could be an effective therapeutic strategy in this respect, and Professor Broz
development. “By better understanding the gasdermin D protein, we hope to eventually help develop inhibitors and assess whether, by blocking the gasdermin D protein, we can prevent inflammation in those types of diseases,” says Professor Broz. The project is largely exploratory at this stage however, with researchers aiming to define, in vivo, the role of gasdermin D in the inflammasomedependent bacterial host defence. “We hope to provide more insights into the gasdermin D protein, and to pinpoint where it is important,” continues Professor Broz.
Pyroptosis
Apoptosis
Time-lapse microscopy images showing a cell dying by apoptosis (upper row) and pyroptosis (lower row).
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