NOD-like receptor (NLR) family members are intracellular molecules that play a key role in innate sensing. Upon ligand binding in the cytosol, NLRs assemble a multimeric complex that includes the adaptor protein ASC and procaspase-1. This assembled complex, referred to as the inflammasome, drives the production of an active form of caspase-1 that then activates IL-1β and IL-18. Activating mutations in members of the NLR family are associated with sterile inflammatory syndromes referred to as cyropyrin-associated periodic syndromes (CAPS). Previous studies have shown that mutations in the NLR family member NLRP3 are associated with CAPS and the overproduction of IL-1β. This raises the question of whether CAPS may be caused by mutations in other NLR family members.

In this issue, Kitamura et al. describe a Japanese family with a sterile autoinflammatory syndrome. Affected family members developed a clinical syndrome characterized by intermittent episodes of fever and cold-induced urticaria and arthralgias. Inheritance of this syndrome was autosomal dominant, and this led the investigators to search for a genetic cause using whole exome sequencing (WES). Interestingly, the results of WES showed no identifiable mutation in the NLRP3 gene. So the team searched the WES data for other rare variants that could explain the syndrome. WES in a single autosomal dominant family can be quite challenging, as a large number of rare variants will track with disease within a family. Here, the investigators used a combination of genetic linkage and gene function analyses to home in on NLRC4. The mutation (H443P) in the affected patients lies in a highly conserved portion of the nucleotide binding domain of NLRC4, and the mutant form of NLRC4 is associated with spontaneous oligomerization, enhanced activation of caspase-1, and hyper-activation of IL-1β. The team also developed an in vivo mouse model of the disease by expressing a mutant form of NLRC4 under the control of the invariant chain (Ii) promoter in a transgene. The transgenic mice developed dermatitis, arthritis, and splenomegaly—features that overlap to some extent with the clinical features of the patients.

A number of important questions remain to be answered. First, are there distinct features of the NLRC4 mutation–associated syndromes? Interestingly, in two other recent reports of families with NLRC4 mutations, the phenotype was more severe and included gastrointestinal complications that were not observed in the patients in this study. NLRC4 is known to be involved in bacterial sensing through detection of flagellin or components of the bacterial type 3 secretion system, and it may be the case that more severe mutations in NLRC4 may provoke a phenotype in the gut related to the sensing of bacterial flora. Second, how do the rare mutations in NLRC4 lead to autoactivation at a molecular level?

This study, along with two other recently published reports, firmly establishes that mutations in the NLR family member NLRC4 can provoke an autoinflammatory syndrome. The identification of these disease-causing mutations will be a rich resource for further unraveling how NLRC4-related assembly occurs and is controlled.

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J. Exp. Med.