Inflammatory caspase regulation: maintaining balance between inflammation and cell death in health and disease

Abstract

Members of the mammalian inflammatory caspase family, including caspase-1, caspase-4, caspase-5, caspase-11, and caspase-12, are key regulators of the innate immune response. Most studies to date have focused on the role of caspase-1 in the maturation of the proinflammatory cytokine interleukin-1β and its upstream regulation by the inflammasome signaling complexes. However, an emerging body of research has supported a role for caspase-4, caspase-5, and caspase-11 in both regulating caspase-1 activation and inducing the inflammatory form of cell death called pyroptosis. This inflammatory caspase pathway appears essential for the regulation of cytokine processing. Consequently, insight into this noncanonical pathway may reveal important and, to date, understudied targets for the treatment of autoinflammatory disorders where the inflammasome pathway is dysregulated. Here, we will discuss the mechanisms of inflammasome and inflammatory caspase activation and how these pathways intersect to promote pathogen clearance.

Keywords: ASC; NLRP3; caspase-1; inflammasome; interleukin-1β.

Figure 1:

Domain organization of the inflammasome components, the inflammatory caspases and the inflammatory caspase substrates described in this review.

Figure 2:

Model for inflammatory caspase activation. PAMPs and DAMPs activate TLRs on the plasma membrane, which induces expression of pro-IL-18, pro-IL-1β, and certain upstream inflammasome components including NLRP3. PAMPs and DAMPs trigger inflammasome assembly by inducing a conformational change in the NLR protein (NLRP3 is shown as an example) followed by oligomerization. NLRP3 recruits ASC bringing several caspase-1 molecules into proximity facilitating dimerization and activation. Once activated, caspase-1 cleaves IL-1β and IL-18 that are released from the cell through the GSDMD pore. Caspase-4/−5/−11 are activated directly by intracellular LPS to cleave GSDMD.