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.

Metrics

  • 1,740
    views
  • 385
    downloads
  • 10
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Immunology and Inflammation
    2. Microbiology and Infectious Disease
    Xu Zheng, Shi Yu ... Guangxun Meng
    Research Article

    Innate immune responses triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play pivotal roles in the pathogenesis of COVID-19, while host factors including proinflammatory cytokines are critical for viral containment. By utilizing quantitative and qualitative models, we discovered that soluble factors secreted by human monocytes potently inhibit SARS-CoV-2-induced cell-cell fusion in viral-infected cells. Through cytokine screening, we identified that interleukin-1β (IL-1β), a key mediator of inflammation, inhibits syncytia formation mediated by various SARS-CoV-2 strains. Mechanistically, IL-1β activates RhoA/ROCK signaling through a non-canonical IL-1 receptor-dependent pathway, which drives the enrichment of actin bundles at the cell-cell junctions, thus prevents syncytia formation. Notably, in vivo infection experiments in mice confirmed that IL-1β significantly restricted SARS-CoV-2 spread in the lung epithelium. Together, by revealing the function and underlying mechanism of IL-1β on SARS-CoV-2-induced cell-cell fusion, our study highlights an unprecedented antiviral function for cytokines during viral infection.

    1. Immunology and Inflammation
    Ning Song, Hang Gao ... Wenlong Zhang
    Research Article

    Gout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of ‘younger’ microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.