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Cited by 773Inflammasome and immune disordersImmune Response and InflammationIL-33, ST2, and ILC Pathways

The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation

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Franklin, Bernardo S, Bossaller, Lukas, De Nardo, Dominic, Ratter, Jacqueline M, Stutz, Andrea, Engels, Gudrun, Brenker, Christoph, Nordhoff, Mark +17 more·2014·Nature Immunology
DOI 10.1038/ni.2913PMC PMC4116676
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Abstract

Microbes or danger signals trigger inflammasome sensors, which induce polymerization of the adaptor ASC and the assembly of ASC specks. ASC specks recruit and activate caspase-1, which induces maturation of the cytokine interleukin 1β (IL-1β) and pyroptotic cell death. Here we found that after pyroptosis, ASC specks accumulated in the extracellular space, where they promoted further maturation of IL-1β. In addition, phagocytosis of ASC specks by macrophages induced lysosomal damage and nucleation of soluble ASC, as well as activation of IL-1β in recipient cells. ASC specks appeared in bodily fluids from inflamed tissues, and autoantibodies to ASC specks developed in patients and mice with autoimmune pathologies. Together these findings reveal extracellular functions of ASC specks and a previously unknown form of cell-to-cell communication.

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Crossref · 10.1038/ni.2913

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  • Cell membrane rupture upon pyroptosis leads to the release of DAMPs such as HMGB1 as well as ASC specks into the extracellular space.

    “Cell membrane rupture upon pyroptosis leads to the release of DAMPs such as HMGB1 as well as ASC specks into the extracellular space [69, 70].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [70]

    The Results section, “Extracellular ASC specks accumulate after pyroptosis” (page unavailable), links pyroptotic membrane disintegration to ASC specks appearing in the extracellular space. Our copy does not identify HMGB1 or report its release as a DAMP, so that part of the sentence is not supported by this source. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ASC specks can be recognized by neighboring microglia as a danger signal and induce inflammatory responses including activation of the NLRP3 inflammasome, thereby propagating inflammation.

    “They can also be recognized by neighboring microglia as a danger signal and induce inflammatory responses including activation of the NLRP3 inflammasome, thereby propagating inflammation [70–72].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [70]

    The Results section, “Extracellular specks constitute a danger signal” (page not available), reports that recipient macrophages take up ASC specks and release IL-1β, potentially propagating inflammatory signals. The paper does not establish this response in neighboring microglia. Its “ASC specks induce inflammatory responses in vivo” section finds that NLRP3 contributes to the response, but that IL-1β activation is not fully dependent on NLRP3 inflammasome activation. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • ASC specks released from pyroptotic cells accumulate in the extracellular space, where they can potentially continue to process and activate pro-caspase-1 and pro-IL-1β.

    “These ASC specks released from the pyroptotic cell accumulate in the extracellular space, where they can potentially continue to process and activate pro-caspase-1 and pro-IL-1β [70].”

    From Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease (2023) · cites this paper as [70]

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Authors
Franklin, B. S., Bossaller, L., De Nardo, D., Ratter, J. M., Stutz, A., Engels, G., Brenker, C., Nordhoff, M., Mirandola, S. R., Al-Amoudi, A., Mangan, M. S., Zimmer, S., Monks, B. G., Fricke, M., Schmidt, R. E., Espevik, T., Jones, B., Jarnicki, A. G., Hansbro, P. M., Busto, P., Marshak-Rothstein, A., Hornemann, S., Aguzzi, A., Kastenmüller, W., & Latz, E.
Affiliations
  • University of Bonn (DE)
  • University of Massachusetts Chan Medical School (US)
  • German Center for Neurodegenerative Diseases (DE)
  • Medizinische Hochschule Hannover (DE)
  • Norwegian University of Science and Technology (NO)
  • University of Newcastle Australia (AU)
  • University Hospital Zurich (CH)
Corresponding author
Latz, Eicke
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2014-06-22
Volume
15
Issue
8
Pages
727-737
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/ni.2913
PMC
PMC4116676
OpenAlex
W2032370476
Cited by
773
References
9
Citations by year
2026: 45 · 2025: 35 · 2024: 56 · 2023: 59 · 2022: 86 · 2021: 75 · 2020: 66 · 2019: 80 · 2018: 61 · 2017: 63 · 2016: 67 · 2015: 57 · 2014: 22
FWCI
28.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • UTS ePRESS (University of Technology Sydney) (submittedVersion)
  • DZNE Pub (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • NOVA (University of Newcastle Australia) (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • National Heart, Lung, and Blood Institute (R01HL093262, R01HL112661)
  • National Institute of Allergy and Infectious Diseases (R01AI083713)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
Keywords
ASC, inflammasome, ASC specks, pyroptosis, caspase-1, macrophage phagocytosis, lysosomal damage, autoantibodies, autoimmune disease, cell-to-cell communication
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Amino Acid Chloromethyl Ketones, Animals, Antibodies, Autoantibodies, Autoimmune Diseases, Carrier Proteins, Cell Communication, Cytoskeletal Proteins, Humans, Inflammation, Lysosomes, Macrophages, Mice, Inbred BALB C, Mice, Inbred C57BL, Phagocytosis, Prions, Pseudomonas aeruginosa, Pseudomonas Infections, Signal Transduction, Apoptosis, Mice, Knockout, Caspase 1, Apoptosis Regulatory Proteins, Mice, CARD Signaling Adaptor Proteins, Interleukin-1beta, Inflammasomes, Caspase Inhibitors

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