1. Immunology and Inflammation

Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome

  1. Tadayoshi Karasawa  Is a corresponding author
  2. Takanori Komada
  3. Naoya Yamada
  4. Emi Aizawa
  5. Yoshiko Mizushina
  6. Sachiko Watanabe
  7. Chintogtokh Baatarjav
  8. Takayoshi Matsumura
  9. Masafumi Takahashi  Is a corresponding author
  1. Jichi Medical University, Japan
https://doi.org/10.7554/eLife.75166
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Cite this article
  1. Tadayoshi Karasawa
  2. Takanori Komada
  3. Naoya Yamada
  4. Emi Aizawa
  5. Yoshiko Mizushina
  6. Sachiko Watanabe
  7. Chintogtokh Baatarjav
  8. Takayoshi Matsumura
  9. Masafumi Takahashi
(2022)
Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome
eLife 11:e75166.
https://doi.org/10.7554/eLife.75166
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  3. Download .RIS

Abstract

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome caused by mutations of NLRP3 gene encoding cryopyrin. Familial cold autoinflammatory syndrome (FCAS), the mildest form of CAPS, is characterized by cold-induced inflammation induced by the overproduction of IL-1β. However, the molecular mechanism of how mutated NLRP3 causes inflammasome activation in CAPS remains unclear. Here, we found that CAPS-associated NLRP3 mutants form cryo-sensitive aggregates that function as a scaffold for inflammasome activation. Cold exposure promoted inflammasome assembly and subsequent IL-1β release triggered by mutated NLRP3. While K+ efflux was dispensable, Ca2+ was necessary for mutated NLRP3-mediated inflammasome assembly. Notably, Ca2+ influx was induced during mutated NLRP3-mediated inflammasome assembly. Furthermore, caspase-1 inhibition prevented Ca2+ influx and inflammasome assembly induced by the mutated NLRP3, suggesting a feed-forward Ca2+ influx loop triggered by mutated NLRP3. Thus, the mutated NLRP3 forms cryo-sensitive aggregates to promote inflammasome assembly distinct from canonical NLRP3 inflammasome activation.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-8.

Article and author information

Author details

  1. Tadayoshi Karasawa

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    For correspondence
    tdys.karasawa@jichi.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6738-2360

  2. Takanori Komada

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3360-3185

  3. Naoya Yamada

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Emi Aizawa

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    Competing interests
    The authors declare that no competing interests exist.

  5. Yoshiko Mizushina

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9988-5755

  6. Sachiko Watanabe

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    Competing interests
    The authors declare that no competing interests exist.

  7. Chintogtokh Baatarjav

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    Competing interests
    The authors declare that no competing interests exist.

  8. Takayoshi Matsumura

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    Competing interests
    The authors declare that no competing interests exist.

  9. Masafumi Takahashi

    Division of Inflammation Research, Jichi Medical University, Shimotsuke, Japan
    For correspondence
    masafumi2@jichi.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2716-7532

Funding

Japan Society for the Promotion of Science (18K08112)

  • Masafumi Takahashi

Japan Society for the Promotion of Science (21K08114)

  • Masafumi Takahashi

Japan Society for the Promotion of Science (16H01395)

  • Masafumi Takahashi

Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care

  • Tadayoshi Karasawa

Japan Agency for Medical Research and Development

  • Masafumi Takahashi

Ministry of Education, Culture, Sports, Science and Technology

  • Masafumi Takahashi

We declare that the funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Karasawa et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Tadayoshi Karasawa
  2. Takanori Komada
  3. Naoya Yamada
  4. Emi Aizawa
  5. Yoshiko Mizushina
  6. Sachiko Watanabe
  7. Chintogtokh Baatarjav
  8. Takayoshi Matsumura
  9. Masafumi Takahashi
(2022)
Cryo-sensitive aggregation triggers NLRP3 inflammasome assembly in cryopyrin-associated periodic syndrome
eLife 11:e75166.
https://doi.org/10.7554/eLife.75166

Share this article

https://doi.org/10.7554/eLife.75166

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