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⇱ Pyroptosis: host cell death and inflammation | Nature Reviews Microbiology

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Key Points

  • Life or death of individual cells determines health and disease in multi-celled organisms. Cell death is crucial for organogenesis in utero and successful control of host cell populations in healthy tissues, but can also play a part in disease that occurs in response to toxic insults or microbial infection.

  • The cysteine protease family called caspases is composed of both initiators and effectors, have crucial roles in cell death and drive mechanistically distinct modes of cellular demise. The physiological consequences of cell death are determined by the mechanisms employed, which range from relatively benign cellular destruction to alarm-ringing inflammatory recruitment of additional cells and biochemical processes.

  • Microorganism- and host-derived 'danger' signals stimulate formation of a multiprotein complex, termed the inflammasome, which leads to processing and activation of caspase 1. Active caspase 1 causes pyroptosis and is responsible for proteolytic maturation of the inflammatory cytokines interleukin-1Ξ² (IL-1Ξ²) and IL-18.

  • Pyroptosis is characterized by caspase 1-dependent formation of plasma-membrane pores, which leads to pathological ion fluxes that ultimately result in cellular lysis and release of inflammatory intracellular contents.

  • During microbial infection in vivo, caspase 1-dependent processes control pathogen replication, stimulate adaptive immune responses and enhance host survival; however, inappropriate activation of caspase 1 can lead to pathological inflammation.

  • Pathogens have a range of mechanisms for preventing the activation of caspase 1, highlighting its antimicrobial role during infection. Pathogens can directly inhibit caspase 1 activation, induce alternative forms of cell death or regulate production of caspase 1-activating ligands.

Abstract

Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes. Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections. Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease. Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host.

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Figure 1: Pyroptosis, an inflammatory host response.
The alternative text for this image may have been generated using AI.
Figure 2: Sensing of host- and microorganism-derived 'danger' signals leads to two distinct outcomes: cellular activation and cell death.
The alternative text for this image may have been generated using AI.
Figure 3: Components of the inflammasome and visualizing the inflammasome complex.
The alternative text for this image may have been generated using AI.
Figure 4: Caspase 1 activation in health and disease: fighting infection versus pathological inflammation.
The alternative text for this image may have been generated using AI.
Figure 5: Susceptibility to pyroptosis is governed by pathogen and host modulation of caspase 1 activation.
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Acknowledgements

S.L.F. was supported by National Institutes of Health Grants AI47242 and P50 HG02360 and Poncin and Achievement Rewards for College Scientist Fellowships. T.B. was supported by National Institute of General Medical Sciences Public Health Service National Research Service Award Grant T32 GM07270 and a Helen Riaboff Whitely Fellowship.

Author information

Authors and Affiliations

  1. Department of Microbiology, University of Washington, Seattle, 98195, Washington, USA

    Tessa Bergsbaken & Brad T. Cookson

  2. Departments of Molecular and Cellular Biology, University of Washington, Seattle, 98195, Washington, USA

    Susan L. Fink

  3. Laboratory Medicine, University of Washington, Seattle, 98195, Washington, USA

    Brad T. Cookson

Authors
  1. Tessa Bergsbaken
  2. Susan L. Fink
  3. Brad T. Cookson

Corresponding author

Correspondence to Brad T. Cookson.

Glossary

Caspases

A group of cysteine proteases that, based on their physiological roles, can be divided into two groups: those involved in the initiation and execution of apoptosis (caspase 2, 3, 6, 7, 8, 9 and 10) and those that trigger inflammation (caspase 1 and related caspases).

Autophagy

A programme of cellular self-digestion in which cytoplasmic components are sequestered and degraded intracellularly in autophagosomes. Autophagic cell corpses are ultimately removed by phagocytosis.

Oncosis

A caspase-independent pathway of cell death triggered by exposure to toxins or physical damage that features organelle and cell swelling and culminates in cell lysis with release of intracellular contents that stimulate inflammatory responses.

Toll-like receptor

A transmembrane protein that contains a leucine-rich repeat domain and mediates host recognition of pathogen- and danger-associated molecular patterns located in the extracellular milieu or within endosomes.

Nod-like receptor

A protein that contains a leucine-rich repeat domain and mediates host recognition of pathogen- and danger-associated molecular patterns in the host cell cytosol.

Proteasome

A multiprotein complex that recognizes and degrades polyubiquitinated substrates.

Pyronecrosis

Results from Shigella infection at high MOI (multiplicity of infection), morphologically resembles oncosis and is NLRP3-dependent and caspase 1-independent.

Microvesicle

A membrane vesicle of less than 0.5 ΞΌm in diameter that is shed from the plasma membrane of eukaryotic cells.

Necrosis

Does not indicate a specific pathway of cell death, but is a post-mortem description of dead cells that have reached equilibrium with their surroundings.

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Bergsbaken, T., Fink, S. & Cookson, B. Pyroptosis: host cell death and inflammation. Nat Rev Microbiol 7, 99–109 (2009). https://doi.org/10.1038/nrmicro2070

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