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Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation

Nature Reviews Immunology volume 7, pages 31–40 (2007)Cite this article

Key Points

  • Hosts have evolved strategies to detect and respond rapidly to invading microorganisms and host-cell damage or 'danger signals'. The caspase-1 inflammasome is a dynamic complex in which specific NOD-like receptors (NLRs) and adaptor molecules are brought into play, depending on the nature of the primary trigger.

  • ASC (apoptosis-associated speck-like protein containing a CARD) has a central role in the inflammasome. Through homotypic protein–protein interactions with its own CARD (caspase-recruitment domain) and PYD (pyrin domain), ASC is thought to act as a direct bridge between the sensor NALPs (NACHT-, LRR- and pyrin-domain-containing proteins) and the downstream effector caspase-1.

  • The two-signal activation model is derived from studies of the treatment of cultured macrophages with pathogen-associated molecular patterns, which, in the absence of ATP, are insufficient to activate the inflammasome complex. However, infection with bacterial pathogens both in vitro and in vivo does not require ATP to trigger the inflammasome.

  • NALP3 is involved in sensing toxins, 'danger signals' such as gout crystals, Staphylococcus aureus, Listeria monocytogenes, bacterial RNA and trinitrophenylchloride.

  • IPAF (ICE-protease activating factor) is involved in sensing various intracellular bacterial pathogens, such as Salmonella typhimurium, Shigella flexneri and Legionella pneumophila. Flagellin might be one common pathogen-associated molecule that is recognized by IPAF and/or NAIP5 (neuronal apoptosis inhibitor protein 5).

  • ASC is required for the inflammasome recognition of Francisella tularensis.

Abstract

The NOD-like receptors have important roles in innate immunity as intracellular sensors of microbial components and cell injury. It has been proposed that these cytosolic proteins regulate the cysteine protease caspase-1 within a multiprotein complex known as the 'inflammasome'. Activation of caspase-1 leads to the cleavage and activation of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, as well as host-cell death. The analysis of mice that are deficient in various inflammasome components has revealed that the inflammasome is a dynamic entity that is assembled from different adaptors in a stimulus-dependent manner. Here we review recent work on the activation of the inflammasome in response to various bacterial pathogens and tissue damage.

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Figure 1: The combination of two distinct extracellular triggers is needed to induce the robust activation of the caspase-1 inflammasome and subsequent release of IL-1β.
Figure 2: Activation of the NALP3 inflammasome by bacterial and host-derived components.
Figure 3: Activation of the ASC or IPAF inflammasome by bacterial components.
Figure 4: Activation of inflammasomes.

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Acknowledgements

The author thanks T. Henry, I. Brodsky, S. Falkow and D.S. Weiss for critical reading of the manuscript.

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  1. Department of Translational Oncology, Genentech, 1 DNA Way, South San Francisco, 94080, California, USA

    Sanjeev Mariathasan

  2. Department of Microbiology and Immunology, Stanford University, Stanford, 94305, California, USA

    Denise M. Monack

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DATABASES

OMIM

chronic infantile neurological cutaneous and articular syndrome

familial cold urticaria

Muckle–Wells syndrome

Glossary

Flagellin

A protein that arranges itself in a hollow cylinder to form the filament in bacterial flagellum, and is required for bacterial motility and often for virulence.

Zymogen

An inactive enzyme that requires biochemical change to become an active enzyme.

Endogenous pyrogen

A host molecule that can cause fever and is important for host immune defences.

Purinergic receptors

A family of plasma-membrane molecules that are involved in several known cellular functions, such as vascular reactivity, apoptosis and cytokine secretion.

Danger signals

Molecules that alert the innate immune system and trigger defensive immune responses, which are referred to as danger-associated molecular patterns (DAMPs), that indicate cellular stress.

Tularaemia

A zoonotic infectious disease, also called rabbit fever, that is caused by the bacterium Francisella tularensis and is often transmitted to humans by contact with animal tissues or from tick bites. Francisella tularensis is considered a potential bioterrorism agent owing to the low infectious dose (10 organisms) and its ability to be transmitted by aerosols.

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Mariathasan, S., Monack, D. Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 7, 31–40 (2007). https://doi.org/10.1038/nri1997

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