Cited by 3,080Inflammasome and immune disordersImmune Response and InflammationAutoimmune and Inflammatory Disorders Research

Cryopyrin activates the inflammasome in response to toxins and ATP

Mariathasan, Sanjeev, Weiss, David S., Newton, Kim, McBride, Jacqueline, O'Rourke, Karen, Roose-Girma, Meron, Lee, Wyne P., Weinrauch, Yvette +2 more·2006·Nature

Abstract

A crucial part of the innate immune response is the assembly of the inflammasome, a cytosolic complex of proteins that activates caspase-1 to process the proinflammatory cytokines interleukin (IL)-1beta and IL-18. The adaptor protein ASC is essential for inflammasome function, binding directly to caspase-1 (refs 3, 4), but the triggers of this interaction are less clear. ASC also interacts with the adaptor cryopyrin (also known as NALP3 or CIAS1). Activating mutations in cryopyrin are associated with familial cold autoinflammatory syndrome, Muckle-Wells syndrome and neonatal onset multisystem inflammatory disease, diseases that are characterized by excessive production of IL-1beta. Here we show that cryopyrin-deficient macrophages cannot activate caspase-1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor to decrease intracellular K+ levels. The release of IL-1beta in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to Asc-/- macrophages, cells deficient in the gene encoding cryopyrin (Cias1-/-) activated caspase-1 and secreted normal levels of IL-1beta and IL-18 when infected with Gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to Gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate caspase-1 and secrete IL-1beta. Therefore, cryopyrin is essential for inflammasome activation in response to signalling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus or L. monocytogenes.

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Crossref · 10.1038/nature04515

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  • P2RX7 has been linked to inflammasome activation.

    “the latter of which has been linked to inflammasome activation58,59”

    From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [58]

  • This binding elicits activation of the NLRP3 inflammasome in LPS-stimulated macrophages, causing secretion of IL-18 and IL-1β, and may promote maintenance and function of the epithelial barrier.

    “this has been shown to elicit activation of the NLRP3 inflammasome in LPS-stimulated macrophages, which causes secretion of IL-18 (but also of the pro-inflammatory cytokine IL-1β) and may thus promote maintenance and function of the epithelial barrier (Mariathasan et al., 2006; Sutterwala et al., 2014; 2006; Yaron et al., 2015).”
  • Nalp3 detects bacteria through MDP or through bacterial toxins.

    “For example, the presence of bacteria is recognized through binding of the pathogen-associated molecular pattern (PAMP) muramyldipeptide (MDP) or via the action of bacterial toxins (9,10).”
  • Nalp3 can detect endogenous danger signals, including ATP and MSU.

    “In addition to PAMPs, Nalp3 has the extraordinary capacity of sensing endogenous stress-associated danger signals (DAMPs) such as ATP (9) or MSU (7).”
  • In vitro, robust activation of the NLRP3 inflammasome in phagocytic cells pretreated with microbial products or cytokines such as TNF is dependent on the presence of ATP.

    “In vitro, robust activation of the NLRP3 inflammasome in phagocytic cells that were pretreated with microbial products or cytokines such as TNF is dependent on the presence of ATP20.”

    From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [20]

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Authors
Mariathasan, S., Weiss, D. S., Newton, K., McBride, J., O'Rourke, K., Roose-Girma, M., Lee, W. P., Weinrauch, Y., Monack, D. M., & Dixit, V. M.
Affiliations
  • Genentech (US)
  • Stanford Medicine (US)
  • New York University (US)
Corresponding author
Dixit, Vishva M.
Venue
Nature
Published
2006-01-11
Volume
440
Issue
7081
Pages
228-232
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
OpenAlex
W2090859543
Cited by
3,080
References
26
Citations by year
2026: 90 · 2025: 101 · 2024: 129 · 2023: 121 · 2022: 150 · 2021: 152 · 2020: 160 · 2019: 161 · 2018: 155 · 2017: 164 · 2016: 184 · 2015: 179 · 2014: 180 · 2013: 189 · 2012: 173
FWCI
62.33
Type
journal article
Language
en
Open access
closed
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
Keywords
NLRP3, inflammasome, caspase-1, IL-1β, IL-18, ATP, P2X7 receptor, bacterial toxins, maitotoxin, nigericin, bacterial RNA, R837, R848, urate crystals, autoinflammatory disease, innate immunity
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Polyether Toxins, Adenosine Triphosphate, Animals, Carrier Proteins, Cytoskeletal Proteins, Enzyme Activation, Inflammation, Interleukin-1, Listeria monocytogenes, Macrophages, Marine Toxins, Nigericin, Staphylococcus aureus, Toxins, Biological, Signal Transduction, NF-kappa B, Caspase 1, Oxocins, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Extracellular Signal-Regulated MAP Kinases, Apoptosis Regulatory Proteins, Toll-Like Receptors, Mice, CARD Signaling Adaptor Proteins, Nod2 Signaling Adaptor Protein

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