| First Author | Doglio MG | Year | 2023 |
| Journal | Sci Immunol | Volume | 8 |
| Issue | 89 | Pages | eadf4404 |
| PubMed ID | 38000038 | Mgi Jnum | J:343254 |
| Mgi Id | MGI:7564337 | Doi | 10.1126/sciimmunol.adf4404 |
| Citation | Doglio MG, et al. (2023) Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1beta secretion. Sci Immunol 8(89):eadf4404 |
| abstractText | Loss-of-function mutations in the deubiquitinase OTULIN result in an inflammatory pathology termed "OTULIN-related autoinflammatory syndrome" (ORAS). Genetic mouse models revealed essential roles for OTULIN in inflammatory and cell death signaling, but the mechanisms by which OTULIN deficiency connects cell death to inflammation remain unclear. Here, we identify OTULIN deficiency as a cellular condition that licenses RIPK3-mediated cell death in murine macrophages, leading to Nlrp3 inflammasome activation and subsequent IL-1beta secretion. OTULIN deficiency uncoupled Nlrp3 inflammasome activation from gasdermin D-mediated pyroptosis, instead allowing RIPK3-dependent cell death to act as an Nlrp3 inflammasome activator and mechanism for IL-1beta release. Accordingly, elevated serum IL-1beta levels in myeloid-specific OTULIN-deficient mice were diminished by deleting either Ripk3 or Nlrp3. These findings identify OTULIN as an inhibitor of RIPK3-mediated IL-1beta release in mice. |
