The exact sequence of events leading to inflammasome activation is not well understood for all inflammasomes. It is believed that upon stimulation, the respective inflammasome oligomerizes and recruits pro–caspase-1 directly via a CARD homotypic interaction (e.g., NLRP1 or NLRC4 inflammasomes) or indirectly via the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC, or Pycard). In the latter case, NLRP3 or AIM2, for example, interact with ASC via the homotypic interaction of their PYDs. ASC, in turn, interacts with pro–caspase-1 via their CARDs.
In resting cells, caspase-1 is present in a catalytically inactive pro-form. The formation of the inflammasome initiates autocatalytic activation of caspase-1 by mediating the apposition of two or more caspase-1 monomers, resulting in cleavage of the pro-enzyme into a 20-kDa (p20) and a 10-kDa (p10) subunit (14
). The active enzyme then assembles into two heterodimers of p20 and p10 subunits, containing two active sites (15
Caspase-1 was initially known as IL-1–converting enzyme, since its first known substrate, pro–IL-1β, is proteolytically converted into the bioactive cytokine, IL-1β (14
). Mature IL-1β is a potent pyrogen with pleiotropic functions including the activation of lymphocytes and endothelial cells and the initiation of the acute phase response (16
). Due to this repertoire of highly potent pro-inflammatory activities, accidental release of IL-1β would be quite deleterious, which explains the development of a complicated mechanism of regulation in mammals. The regulation of IL-1β secretion includes priming, maturation of both caspase-1 and IL-1β, and release of the active protein (17
Caspase-1 can also cleave other members of the IL-1 family. Caspase-1–mediated cleavage has been shown for pro–IL-18 (18
). The pro-form of this cytokine is constitutively expressed and does not require priming for induction. IL-18 can induce IFN-γ and pro-inflammatory cytokine secretion and activates NK cells. Caspase-1 can also cleave IL-33, another member of the IL-1 family, but in contrast to the other mentioned cytokines, IL-33 is inactivated by caspase-1–mediated processing and activated by another enzyme, calpain (19
The mechanisms leading to secretion of the mature cytokines are not well understood. Several models for their export have been proposed, such as secretion via multivesicular bodies containing exosomes, via shedding of microvesicles from the plasma membrane or directly through the plasma membrane via unidentified transporters (22
Under certain circumstances, release of the cytokines precedes or is concomitant with a caspase-1–induced inflammatory cell death called “pyroptosis”. Recent reviews on cell death in response to infection describe the morphology and significance of pyroptosis in more detail (26
). In brief, pyroptosis shows characteristics of both apoptosis and necrosis. It is a rapid process involving caspase-1–dependent DNA fragmentation and pore formation, which leads to cellular lysis (28
). Other effector mechanisms downstream of caspase-1 are currently under investigation. For example, caspase-1 was reported to inhibit the glycolysis pathway by cleaving key enzymes, including aldolase and glyceraldehyde-3-phosphate dehydrogenase (29
). This process and cleavage of the apoptosis effector caspase-7 by caspase-1 (30
) might be starting points for this special form of cell death.
However, cell death is not found in all cases of caspase-1 activation. In response to pore-forming toxins (via the NLRP3 inflammasome; see below), caspase-1 can promote cell survival by activating lipid biosynthesis in Chinese hamster ovarian cells and HeLa cells (31
). This suggests a possible switch between cell death and repair after activation of caspase-1. A cell type–specific regulation might be an alternative explanation. A recent report suggests that caspase-1 is not only important for cleavage of substrates, but also regulates unconventional protein secretion. Caspase-1 influences the release of many proteins without signal sequences, including pro–IL-1α and other mediators involved in tissue repair (32