Inflammasome inhibition under physiological and pharmacological conditions

Our plain-English summary of Inflammasome inhibition under physiological and pharmacological conditions, by E.A. Caseley, J.A. Poulter, F. Rodrigues, et al (Genes and Immunity, 2020).

The study

• Authors: E.A. Caseley, J.A. Poulter, F. Rodrigues, Immunome Project Consortium for Autoinflammatory Disorders (ImmunAID), M.F. McDermott
• Journal: Genes and Immunity
• Published: 2020;21(4):211-223
• Type of article: Review
• Cited by: 37 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This article was a review, not an original study. The authors summarised published research on the NLRP3 inflammasome, a group of immune proteins that drives inflammation. It covered the body's own (physiological) inhibitors of NLRP3, how mutations causing cryopyrin-associated periodic syndromes (CAPS) affect its regulation, its molecular structure, and drugs that block it. It did not study asbestos. Mesotheliomas appeared only once, in a list of cancers that another paper (Moossavi et al.) linked to NLRP3 activation. Using the INFEVERS registry, the authors counted 69 of 109 (63.3%) pathogenic or likely pathogenic NLRP3 mutations in the NACHT domain. They said these mutations are predicted to impair inhibition by small molecules that target that domain, such as MCC950. They described NLRP3 inhibitors in clinical trials. One example was a phase II rheumatoid arthritis study of MCC950 that was interrupted because of liver enzyme elevation. The authors concluded that fully understanding how NLRP3 is negatively regulated could benefit human health.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review of published literature
• Who was studied: Not applicable: a literature review with no study population of its own
• Exposure: Not asbestos. The review concerned physiological and pharmacological inhibitors of the NLRP3 inflammasome.
• Main results:
  • The authors reported that, according to the INFEVERS registry, 69 of 109 (63.3%) pathogenic or likely pathogenic NLRP3 mutations lie in the NACHT domain. They said these mutations are predicted to impair inhibition by small molecules targeting that domain, such as MCC950.
  • Mesotheliomas were mentioned only once, in the abstract, among cancers linked to NLRP3 activation. The link was credited to another paper (Moossavi et al.), not examined in this review.
  • Among NLRP3 inhibitors that have been tested in people, the review reported that a phase II study of MCC950 in rheumatoid arthritis was interrupted because of liver enzyme elevation in the treatment group. That study was cited from other sources.
  • The authors said that because the NLRP3 structure had only recently been determined, it was too early to say whether structure-based drug design would be adopted for NLRP3 inhibitors.
• The authors' conclusion: The authors concluded that fully understanding the mechanisms by which the NLRP3 inflammasome is negatively regulated has potential benefits for human health.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Cytokine, Fibrosis, Mesothelioma, Pathology.

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