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Primer: inflammasomes and interleukin 1β in inflammatory disorders

Nature Clinical Practice Rheumatology volume 4, pages 34–42 (2008)Cite this article

Abstract

Inflammasomes are large, multimeric protein complexes that link the sensing of microbial products and metabolic stress to the proteolytic processing of prointerleukin (pro-IL)-1β to its active form. NALP1 and NALP2 are founding members of the Nod-like receptor family. Other Nod-like receptors, including NALP3 and NOD2, which are associated with inflammatory disorders, have also been described. The NALP1 and NALP3 inflammasomes are located in the cytoplasm and can, therefore, detect intracellular infection through recognition of microbial pathogen-associated molecular patterns. The inflammasome pathways cooperate with Toll-like receptor pathways to mediate a rapid and appropriate response to pathogens and genotoxic stress. Mutations in both pyrin and NALP3 components of inflammasomes are associated with innate-immune-mediated diseases (familial Mediterranean fever and the 'cryopyrinopathies'), and aberrant IL-1β processing has been reported in several autoinflammatory conditions, including Muckle–Wells syndrome, chronic infantile neurologic, cutaneous and articular syndrome/neonatal onset multisystem inflammatory disease, and gout. The effectiveness of IL-1β blockade in treating many of these conditions has transformed the understanding and management of these disorders and also highlighted the role of aberrant IL-1β signaling in other conditions, such as adult-onset Still's disease and systemic juvenile idiopathic arthritis.

Key Points

  • The NALP1 and NALP3 inflammasomes, both located in the cytoplasm, detect intracellular infection and cooperate with Toll-like receptor-mediated pathways to induce a rapid and appropriate response to invading pathogens and genotoxic stress

  • Mutations in either pyrin or NALP3 are associated with susceptibility to innate immune-mediated diseases; aberrant processing of interleukin (IL)-1β occurs in all the 'cryopyrinopathies', as well as in gout and pseudogout

  • IL-1β blockade is remarkably effective for many of these conditions; however, IL-1β antagonists with higher affinities and longer half-lives than anakinra are required

  • Further investigations into the role of inflammasomes in the pathogenesis of several autoimmune conditions, such as type 1 diabetes and neoplastic conditions, can be expected

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Figure 1: Domain structure of several Nod-like receptors (NLRs).
Figure 2: Activation of the NALP3 inflammasome.

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Authors and Affiliations

  1. LD Church is a Postdoctoral Research Fellow in the Rheumatology Research Unit at the Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, UK,

    Leigh D Church

  2. GP Cook is a Principal Research Fellow and MF McDermott is a Professor of Experimental Rheumatology.,

    Graham P Cook & Michael F McDermott

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  1. Leigh D Church
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Correspondence to Michael F McDermott.

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Church, L., Cook, G. & McDermott, M. Primer: inflammasomes and interleukin 1β in inflammatory disorders. Nat Rev Rheumatol 4, 34–42 (2008). https://doi.org/10.1038/ncprheum0681

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