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Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion

M Giulia Doglio1,2, Lien Verboom2,3, Emily Ruilova Sosoranga1,2

  • 1Department of Internal Medicine and Paediatrics, Ghent University, 9052 Ghent, Belgium.

Science Immunology
|November 24, 2023
PubMed

Insights

Loss-of-function mutations in OTULIN cause autoinflammatory syndrome. OTULIN deficiency triggers RIPK3-mediated cell death, activating the Nlrp3 inflammasome and IL-1β release in macrophages.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Loss-of-function mutations in the deubiquitinase OTULIN cause OTULIN-related autoinflammatory syndrome (ORAS).
  • OTULIN is crucial for inflammatory and cell death signaling, but its precise role in linking cell death to inflammation is unknown.

Purpose of the Study:

  • To elucidate the mechanisms by which OTULIN deficiency connects cell death to inflammation.
  • To identify the role of OTULIN in regulating RIPK3-mediated cell death and Nlrp3 inflammasome activation.

Main Methods:

  • Utilizing genetic mouse models with myeloid-specific OTULIN deficiency.
  • Investigating the activation of the Nlrp3 inflammasome and IL-1β secretion.
  • Analyzing the interplay between OTULIN, RIPK3, and gasdermin D in macrophage cell death.

Main Results:

  • OTULIN deficiency licenses RIPK3-mediated cell death in murine macrophages.
  • This RIPK3-dependent cell death activates the Nlrp3 inflammasome, leading to IL-1β secretion.
  • OTULIN deficiency uncoupled Nlrp3 inflammasome activation from gasdermin D-mediated pyroptosis.

Conclusions:

  • OTULIN acts as an inhibitor of RIPK3-mediated IL-1β release in mice.
  • OTULIN deficiency promotes inflammation by linking RIPK3-dependent cell death to Nlrp3 inflammasome activation.
  • Targeting OTULIN may offer therapeutic strategies for inflammatory diseases.

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