| Autor: |
Nurmi, Katariina, Silventoinen, Kristiina, Keskitalo, Salla, Rajamäki, Kristiina, Kouri, Vesa-Petteri, Kinnunen, Matias, Jalil, Sami, Maldonado, Rocio, Wartiovaara, Kirmo, Nievas, Elma Inés, Denita-Juárez, Silvina Paola, Duncan, Christopher J.A., Kuismin, Outi, Saarela, Janna, Romo, Inka, Martelius, Timi, Parantainen, Jukka, Beklen, Arzu, Bilicka, Marcelina, Matikainen, Sampsa, Nordström, Dan C., Kaustio, Meri, Wartiovaara-Kautto, Ulla, Kilpivaara, Outi, Klein, Christoph, Hauck, Fabian, Jahkola, Tiina, Hautala, Timo, Varjosalo, Markku, Barreto, Goncalo, Seppänen, Mikko R.J., Eklund, Kari K. |
| Zdroj: |
Cell Reports Medicine; April 2024, Vol. 5 Issue: 4 |
| Abstrakt: |
In monogenic autoinflammatory diseases, mutations in genes regulating innate immune responses often lead to uncontrolled activation of inflammasome pathways or the type I interferon (IFN-I) response. We describe a mechanism of autoinflammation potentially predisposing patients to life-threatening necrotizing soft tissue inflammation. Six unrelated families are identified in which affected members present with necrotizing fasciitis or severe soft tissue inflammations. Exome sequencing reveals truncating monoallelic loss-of-function variants of nuclear factor κ light-chain enhancer of activated B cells(NFKB1) in affected patients.In patients’ macrophages and in NFKB1-variant-bearing THP-1 cells, activation increases both interleukin (IL)-1β secretion and IFN-I signaling. Truncation of NF-κB1 impairs autophagy, accompanied by the accumulation of reactive oxygen species and reduced degradation of inflammasome receptor nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein 3 (NLRP3), and Toll/IL-1 receptor domain-containing adaptor protein inducing IFN-β (TRIF), thus leading to combined excessive inflammasome and IFN-I activity. Many of the patients respond to anti-inflammatory treatment, and targeting IL-1β and/or IFN-I signaling could represent a therapeutic approach for these patients. |
| Databáze: |
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