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Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis

Lookup NU author(s): Dr Christopher DuncanORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2024 The AuthorsIn 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.

Publication metadata

Author(s): Nurmi K, Silventoinen K, Keskitalo S, Rajamaki K, Kouri V-P, Kinnunen M, Jalil S, Maldonado R, Wartiovaara K, Nievas EI, Denita-Juarez SP, Duncan CJA, Kuismin O, Saarela J, Romo I, Martelius T, Parantainen J, Beklen A, Bilicka M, Matikainen S, Nordstrom DC, Kaustio M, Wartiovaara-Kautto U, Kilpivaara O, Klein C, Hauck F, Jahkola T, Hautala T, Varjosalo M, Barreto G, Seppanen MRJ, Eklund KK

Publication type: Article

Publication status: Published

Journal: Cell Reports Medicine

Year: 2024

Volume: 5

Issue: 4

Print publication date: 16/04/2024

Online publication date: 08/04/2024

Acceptance date: 18/03/2024

Date deposited: 17/04/2024

ISSN (electronic): 2666-3791

Publisher: Cell Press

URL: https://doi.org/10.1016/j.xcrm.2024.101503

DOI: 10.1016/j.xcrm.2024.101503

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