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Truncating NFKB1variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis

Authors :
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.
Source :
Cell Reports Medicine; April 2024, Vol. 5 Issue: 4
Publication Year :
2024

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.

Details

Language :
English
ISSN :
26663791
Volume :
5
Issue :
4
Database :
Supplemental Index
Journal :
Cell Reports Medicine
Publication Type :
Periodical
Accession number :
ejs66064739
Full Text :
https://doi.org/10.1016/j.xcrm.2024.101503