The genetic defect in patients with Muckle-Wells syndrome — a severe inflammatory disorder that can be treated with an interleukin-1 (IL-1) receptor antagonist — is found in the gene encoding NALP3. Now, work from Jürg Tschopp's laboratory, published in Immunity, has provided a molecular mechanism by which NALP3 influences the production of IL-1β.

The NALP3 inflammasome. NALP3 interacts with apoptosis-associated speck-like protein containing a CARD (ASC) through a pyrin domain (PYD)-mediated protein–protein interaction and by way of its NACHT domain with the FIIND domain of Cardinal. Caspase-associated recruitment domain (CARD)-mediated protein–protein interactions enable ASC and Cardinal to associate with caspase-1. LRRs, leucine rich repeats; NAD, NALP-associated domain.

Active IL-1β is generated by cleavage of its inactive precursor, pro-IL-1β, by caspase-1. Recently, this process has been shown to involve protein scaffolds, known as the inflammasome, generated by caspase-associated recruitment domain (CARD)- and pyrin domain (PYD)-mediated protein–protein interactions. For example, the CARD of NALP1 is involved in recruiting caspase-5, whereas the PYD of NALP1 associates with caspase-1 via an adaptor protein, apoptosis-associated speck-like protein containing a CARD (ASC).

The CARD-containing region of NALP1 is missing in the other NALP-family members. The authors therefore investigated whether Cardinal, a protein with structural homology to the missing segment, could interact with other NALP proteins, and found that Cardinal co-immunoprecipitated with both NALP2 and NALP3. NALP2 and NALP3 were also shown to associate with ASC, and the CARD of Cardinal was shown to associate with caspase-1. These results indicate that NALP3 could form an inflammasome — consisting of ASC, Cardinal and caspase-1 — capable of processing pro-IL-1β (see figure).

The existence of a NALP3 inflammasome that can produce IL-1β, and the severe inflammatory phenotype of Muckle-Wells patients, suggest that the Muckle-Wells NALP3 mutation could result in constitutive activation of the NALP3 inflammasome. Indeed, the authors showed that monocytes isolated from a Muckle-Wells patient produced IL-1β even in the absence of stimulation, whereas monocytes from healthy individuals only produced IL-1β after activation with lipopolysaccharide. This study therefore provides the first evidence of a causative mechanism of Muckle-Wells syndrome.