Inflammasomes as polyvalent cell death platforms

Abstract

Inflammasomes are multi-protein platforms that are organized in the cytosol to cope with pathogens and cellular stress. The pattern recognition receptors NLRP1, NLRP3, NLRC4, AIM2 and Pyrin all assemble canonical platforms for caspase-1 activation, while caspase-11-dependent inflammasomes respond to intracellular Gram-negative pathogens. Inflammasomes are chiefly known for their roles in maturation and secretion of the inflammatory cytokines interleukin-(IL)1β and IL18, but they can also induce regulated cell death. Activation of caspases 1 and 11 in myeloid cells can trigger pyroptosis, a lytic and inflammatory cell death mode. Pyroptosis has been implicated in secretion of IL1β, IL18 and intracellular alarmins. Akin to these factors, it may have beneficial roles in controlling pathogen replication, but become detrimental in the context of chronic autoinflammatory diseases. Inflammasomes are increasingly implicated in induction of additional regulated cell death modes such as pyronecrosis and apoptosis. In this review, we overview recent advances in inflammasome-associated cell death research, illustrating the polyvalent roles of these macromolecular platforms in regulated cell death signaling.

Keywords: Apoptosis; Caspase-1; Caspase-11; Cell death; Inflammasome; Inflammation; Pyroptosis.

Fig. 1

Schematic representation of the inflammasome pathways resulting in pyroptosis. Pyroptosis as a regulated lytic cell death mode of myeloid cells is induced in response to a wide variety of endogenous, environmental, and pathogen-derived triggers downstream of inflammasome-associated activation of caspases 1 or 11 in mice, or that of the orthologous caspases 1, 4, and 5 in humans. While the PYD-based NLRP3, AIM2, and Pyrin platforms require the bipartite adaptor protein ASC to recruit and activate caspase-1, the CARD-based NLRP1b and NLRC4 inflammasomes trigger caspase-1-dependent pyroptosis independently of ASC. Both caspases 1 and 11 engage pyroptosis directly by cleaving its substrate gasdermin D. The mechanism by which gasdermin D triggers pyroptosis is currently unknown

Fig. 2

Scheme of the morphological and biochemical features of pyroptosis and apoptosis. These forms of cell death represent two very distinct forms of regulated cell death in terms of their final outcome, but share some important characteristics related to their signaling events (highlighted in green boxes)

Fig. 3

Representation of inflammasomes as cell death switches. While engagement of NLRP3, AIM2 and NLRC4 leads to pyroptosis in the presence of caspase-1, lack of this inflammatory caspase deviates the response towards caspase-8-dependent apoptosis. Importantly, NLRC4 is able to activate caspase-1 in the absence of the adaptor ASC, but the apoptotic phenotype is highly dependent on the adaptor protein. Considering the downstream effects of pyroptosis and apoptosis, inflammasome engagement could potentially play contrasting roles in immune response depending on the expression level of caspase-1