1. Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis.
- Author
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Nurmi K, Silventoinen K, Keskitalo S, Rajamäki K, Kouri VP, Kinnunen M, Jalil S, Maldonado R, Wartiovaara K, Nievas EI, Denita-Juárez SP, Duncan CJA, Kuismin O, Saarela J, Romo I, Martelius T, Parantainen J, Beklen A, Bilicka M, Matikainen S, Nordström DC, Kaustio M, Wartiovaara-Kautto U, Kilpivaara O, Klein C, Hauck F, Jahkola T, Hautala T, Varjosalo M, Barreto G, Seppänen MRJ, and Eklund KK
- Subjects
- Humans, Inflammasomes metabolism, NLR Family, Pyrin Domain-Containing 3 Protein genetics, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Immunity, Innate, Inflammation metabolism, NF-kappa B p50 Subunit, Fasciitis, Necrotizing, Interferon Type I
- Abstract
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., Competing Interests: Declaration of interests C.J.A.D. has provided consultative advice to Synairgen on behalf of Newcastle University., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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