Caspase-1 is a proinflammatory
enzyme that is essential in many inflammatory conditions including infectious, autoimmune, and autoinflammatory disorders. The
inflammation is mainly mediated by the generation of
inflammasomes that activate caspase-1 and subsequently
interleukin (IL)-1β and
IL-18. In addition, homotypic CARD/CARD interaction of
procaspase-1 with RIP2 and thereby activation of the NF-κB pathways may play some role in the
inflammation. However, normally, this pathway seems to become downregulated rapidly by the cleavage and excretion of RIP2 by active (pro-)caspase-1. In patients with unexplained recurrent systemic
inflammation, CASP1 variants were detected, which often destabilized the caspase-1 dimer interface. Obviously, the resulting decreased or abrogated enzymatic activity and IL-1β production did not prevent the febrile episodes. As an unexpected finding, the inactive
procaspase-1 variants significantly enhanced proinflammatory signaling by increasing RIP2 mediated NF-κB activation in an in vitro cell transfection model. A likely reason is the failure of inactive
procaspase-1 to cleave bound RIP2 and also to mediate its excretion out of the intracelluar space thereby keeping the RIP2-NF-κB pathway upregulated. Hence, proinflammatory effects of enzymatically inactive
procaspase-1 variants may partially explain the inflammatory episodes of the patients.