In this model, the 'flexible loops' of caspase-1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored.
In addition to the regulatory role of pyrin for caspase-1, the cleavage of pyrin provides an important clue not only in understanding the molecular pathogenesis of FMF but also in developing new therapeutic targets for FMF.
Caspase-1 was constitutively activated in knockin macrophages and active IL-1β was secreted when stimulated with lipopolysaccharide alone, which is also observed in FMF patients.
Likewise, LPS/ATP induced caspase-1-dependent IL-1β release at significantly lower amounts in the FMF group (1182±192 versus 2134±245pg/mL in controls, p=0.004).