The Inflammasomes

Innate immune cells such as macrophages and dendritic cells produce potent inflammatory cytokines to mount an appropriate immune response against microbial threats. The related cytokines interleukin (IL)-1b and IL-18 are generated as cytosolic precursors that require cleavage by the cysteine protease caspase-1 to generate biologically active IL-1b and IL-18. Hence, mice lacking caspase-1 are defective in the maturation and secretion of IL-1b and IL-18 [1]. Caspase-1 itself is generated as an inactive precursor protein that contains a ‘‘caspase activation and recruitment domain’’ (CARD) motif in its N-terminus, which is essential for bringing two or more zymogens sufficiently close to induce their autocatalytic activation, a process believed to occur in large cytosolic protein complexes termed ‘‘inflammasomes’’. Most inflammasomes contain a member of the nucleotide binding and oligomerization domain (NOD)-like receptor (NLR) family. These proteins are thought to function as sensors that detect conserved microbial components in intracellular compartments, similar to the role of mammalian Toll-like receptors (TLRs) at the cell surface and within endosomes [2]. NLRs share a domain organization that usually includes (1) an amino-terminal protein– protein interaction domain such as a CARD or pyrin domain; (2) an intermediary NACHT domain that is required for nucleotide binding and self-oligomerization; and (3) a variable number of carboxyterminal leucine-rich repeat (LRR) motifs involved in sensing pathogen molecules. In general, the pathogen-associated molecular patterns (PAMPs) recognized by NLRs and TLRs are vital for microbial survival, representing either nucleic acid structures unique to microbes or cell wall components alien to mammalian cells. The bipartite adaptor protein ASC plays a central role in the interaction between NLRs and caspase-1 in each of these inflammasome complexes. As a consequence, caspase-1 activation and the production of IL-1b and IL-18 are abolished in ASCdeficient macrophages that are infected with intracellular bacteria or stimulated with a combination of microbial ligands and ATP [3]. ASC has a specific role in caspase-1 activation because secretion of the cytokines TNF-a and IL-6 is not affected by ASC deficiency. Genetic studies in mice suggest that at least four inflammasomes of distinct composition are formed in vivo in a stimulus-dependent manner (Figure 1): the IPAF inflammasome [3–5], the NALP1 inflammasome [6], the Cryopyrin/NALP3 inflammasome [7–9], and a fourth inflammasome triggered by Francisella tularensis infection [8,10]. Biochemical studies suggested the existence of an additional inflammasome containing NALP2 [11,12], although specific ligands for this inflammasome remain to be identified. In addition to these NLRs, the HIN-200 protein absent in melanoma 2 (AIM2) was recently shown to trigger caspase-1 activation in response to cytoplasmic double-stranded DNA (dsDNA) [13–16].