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Inflammasome inhibition under physiological and pharmacological conditions

Genes & Immunity volume 21, pages 211–223 (2020)Cite this article

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Abstract

Inflammasomes are key regulators of the host response against microbial pathogens, in addition to limiting aberrant responses to sterile insults, as mediated by environmental agents such as toxins or nanoparticles, and also by endogenous danger signals such as monosodium urate, ATP and amyloid-β. To date at least six different inflammasome signalling platforms have been reported (Bauernfeind & Hornung, EMBO Mol Med. 2013;5:814–26; Broz & Dixit, Nat Rev Immunol. 2016;16:407). This review focuses on the complex molecular machinery involved in activation and regulation of the best characterised inflammasome, NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), and the development of molecular agents to modulate NLRP3 inflammasome function. Activation of the NLRP3 inflammasome induces inflammation via secretion of interleukin-1β (IL-1β) and interleukin-18 (IL-18) proinflammatory cytokines, with orchestration of pyroptotic cell death, to eliminate invading microbial pathogens. This field has gradually moved from an emphasis on monogenic autoinflammatory conditions, such as cryopyrin-associated periodic syndromes (CAPS), to the broad spectrum of innate immune-mediated disease. NLRP3 inflammasome activation is also linked to a range of common disorders in humans including type 2 diabetes (Krainer et al., J Autoimmun. 2020:102421), cystic fibrosis (Scambler et al., eLife. 2019;8), myocardial infarction, Parkinson’s disease, Alzheimer’s disease (Savic et al., Nat Rev Rheumatol. 2020:1–16) and cancers such as mesotheliomas and gliomas (Moossavi et al., Mol Cancer. 2018;17:158). We describe how laboratory-based assessment of NLRP3 inflammasome activation is emerging as an integral part of the clinical evaluation and treatment of a range of undifferentiated systemic autoinflammatory disorders (uSAID) (Harrison et al., JCI Insight. 2016;1), where a DNA-based diagnosis has not been possible. In addition, this review summarises the current literature on physiological inhibitors and features various pharmacological approaches that are currently being developed, with potential for clinical translation in autoinflammatory and immune-mediated conditions. We discuss the possibilities of rational drug design, based on detailed structural analyses, and some of the challenges in transferring exciting preliminary results from trials of small-molecule inhibitors of the NLRP3 inflammasome, in animal models of disease, to the clinical situation in human pathology.

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Fig. 1: The NLRP3/NEK7 complex domains and related CAPS mutations.
Fig. 2: PKA-mediated NLRP3 inhibition pathway and the relevant CAPS mutations.
Fig. 3: PKD-mediated NLRP3 activation pathway and the relevant CAPS mutations.
Fig. 4: BTK-mediated NLRP3 modification pathway and the relevant CAPS mutations.
Fig. 5: CAPS mutations affecting NLRP3 sumoylation.
Fig. 6: CAPS mutations affecting NLRP3/NEK7 interactions.

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Acknowledgements

The authors (EC, JP and MMcD) are supported by the EU Horizon 2020 research and innovation program (ImmunAID; grant agreement number 779295); FR is supported the Foundation for Development of Internal Medicine in Europe (FDIME), the European Federation of Internal Medicine (EFIM) and the French National Society for Internal Medicine (SNFMI).

Immunome Project Consortium for Autoinflammatory Disorders (ImmunAID)

Emily A. Caseley1, James A. Poulter1, Michael F. McDermott1, Vassili Soumelis1

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  1. These authors contributed equally: Emily A. Caseley, James A. Poulter, François Rodrigues

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  1. Leeds Institute of Rheumatic and Musculoskeletal Medicine, St James’s University Hospital, Leeds, UK

    Emily A. Caseley, James A. Poulter, François Rodrigues, Emily A. Caseley, James A. Poulter & Michael F. McDermott

  2. AP–HP, Hôpital Tenon, Sorbonne Université, Service de Médecine interne, Centre de Référence des Maladies Auto-inflammatoires et des Amyloses d’origine inflammatoire (CEREMAIA), 75020, Paris, France

    François Rodrigues

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  1. Emily A. Caseley
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  2. James A. Poulter
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  3. François Rodrigues
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  4. Michael F. McDermott
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Immunome Project Consortium for Autoinflammatory Disorders (ImmunAID)

  • Emily A. Caseley
  •  & James A. Poulter

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Correspondence to Michael F. McDermott.

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Members of the Immunome project consortium for Autoinflammatory Disorders (ImmunAID) are listed below Acknowledgements.

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Caseley, E.A., Poulter, J.A., Rodrigues, F. et al. Inflammasome inhibition under physiological and pharmacological conditions. Genes Immun 21, 211–223 (2020). https://doi.org/10.1038/s41435-020-0104-x

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  • DOI: https://doi.org/10.1038/s41435-020-0104-x

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