Truncating NFKB1 variants cause combined NLRP3 inflammasome activation and type I interferon signaling and predispose to necrotizing fasciitis
Katariina Nurmi, Kristiina Silventoinen, Salla Keskitalo, Kristiina Rajamäki, Vesa‐Petteri Kouri, Matias Kinnunen, Sami Jalil, Rocío Maldonado, Kirmo Wartiovaara, Elma Nievas, Silvina Paola Denita-Juárez, C.J. Duncan, Outi Kuismin, Janna Saarela, Inka Romo, Timi Martelius, J. Parantainen, Arzu Beklen, Marcelina Bilicka, Sampsa Matikainen, Dan Nordström, Meri Kaustio, Ulla Wartiovaara‐Kautto, Outi Kilpivaara, Christoph Klein, Fabian Hauck, Tiina Jahkola, Timo Hautala, Markku Varjosalo, Gonçalo Barreto, Mikko Seppänen, Kari K. Eklund
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.