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Inflammation

Switching on the inflammasome

Nature Reviews Immunology volume 6, pages 88–89 (2006)Cite this article

The central component of an inflammasome is a member of the NALP family, and this protein associates with the adaptor protein apoptosis-associated speck-like protein (ASC), which in turn recruits pro-inflammatory-caspase precursors (such as pro-caspase-1). NALP1, NALP2 and NALP3 have been shown to form inflammasomes, and the importance of NALP3 is well established, because mutations in the gene that encodes NALP3 (CIAS1) cause several autoinflammatory disorders. So, three groups of researchers set out to define the role of NALP3 in inflammatory responses. Each group independently generated NALP3-deficient mice and then examined macrophages from these mice for their ability to process pro-caspase-1 or pro-IL-1β and to secrete IL-1β in response to various microbial and non-microbial stimuli.

Núñez and colleagues examined macrophage responses to several Toll-like receptor (TLR) ligands and showed that NALP3 is specifically required for pro-caspase-1 cleavage and IL-1β production in response to the synthetic TLR7 ligands R837 (also known as imiquimod) and R848 (also known as resiquimod). These molecules are structurally similar to purine bases, so the authors also examined macrophage responses to bacterial RNA, which they speculated might be a natural ligand for NALP3, and they obtained similar results. Tschopp and colleagues similarly showed that crystals of monosodium urate (which are also structurally similar to purine bases and have recently been reported to be a danger signal) and calcium pyrophosphate dihydrate (both of which elicit inflammatory responses; known as gout and pseudogout, respectively) induce caspase-1-dependent IL-1β secretion by primed macrophages, and this relies on components of the inflammasome, including NALP3. Dixit and colleagues found that NALP3 is also required for pro-caspase-1 activation by another danger signal, ATP (which, in vivo, is released into the extracellular environment by dying cells), and after exposure to certain Gram-positive bacteria but not certain Gram-negative bacteria.

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ORIGINAL RESEARCH PAPERS

  1. Kanneganti, T.-D. et al. Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 11 Jan 2006 (doi:10.1038/nature04517)

  2. Martinon, F., Pétrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 11 Jan 2006 (doi:10.1038/nature04516)

  3. Mariathasan, S. et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 11 Jan 2006 (doi:10.1038/nature04515)

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Authors
  1. Davina Dadley-Moore
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Dadley-Moore, D. Switching on the inflammasome. Nat Rev Immunol 6, 88–89 (2006). https://doi.org/10.1038/nri1789

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  • DOI: https://doi.org/10.1038/nri1789

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