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

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. [Display omitted] •Patients carrying truncating NFKB1 variants present with hyperinflammatory symptoms•Truncation of NFKB1 enhances inflammasome activation and type I interferon response•Truncation of NFKB1 impairs autophagic degradation•Impaired autophagy leads to accumulation of NLRP3 inflammasome components and TRIF Patients presenting with hyperinflammatory reactions to minor trauma or infection may carry predisposing genetic variants. Nurmi and Silventoinen et al. identify a mechanism of autoinflammation in which truncating variants of NF-κB1 impair autophagic degradation. Failure of autophagy increases inflammasome activation and interferon signaling, thus leading to hyperinflammation.