| First Author | Wang Y | Year | 2023 |
| Journal | Immunity | Volume | 56 |
| Issue | 7 | Pages | 1485-1501.e7 |
| PubMed ID | 37315560 | Mgi Jnum | J:338375 |
| Mgi Id | MGI:7511354 | Doi | 10.1016/j.immuni.2023.05.014 |
| Citation | Wang Y, et al. (2023) Identification of an IL-1 receptor mutation driving autoinflammation directs IL-1-targeted drug design. Immunity 56(7):1485-1501.e7 |
| abstractText | The interleukin 1 (IL-1) pathway signals through IL-1 receptor type 1 (IL-1R1) and emerges as a central mediator for systemic inflammation. Aberrant IL-1 signaling leads to a range of autoinflammatory diseases. Here, we identified a de novo missense variant in IL-1R1 (p.Lys131Glu) in a patient with chronic recurrent multifocal osteomyelitis (CRMO). Patient PBMCs showed strong inflammatory signatures, particularly in monocytes and neutrophils. The p.Lys131Glu substitution affected a critical positively charged amino acid, which disrupted the binding of the antagonist ligand, IL-1Ra, but not IL-1alpha or IL-1beta. This resulted in unopposed IL-1 signaling. Mice with a homologous mutation exhibited similar hyperinflammation and greater susceptibility to collagen antibody-induced arthritis, accompanied with pathological osteoclastogenesis. Leveraging the biology of the mutation, we designed an IL-1 therapeutic, which traps IL-1beta and IL-1alpha, but not IL-1Ra. Collectively, this work provides molecular insights and a potential drug for improved potency and specificity in treating IL-1-driven diseases. |
