The inflammasome

What is it? The inflammasome is a multiprotein complex of more than 700 kDa that is responsible for the activation of caspases 1 and 5, leading to the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18. Two types of inflammasome have been identified to date — the NALP1 inflammasome, composed of NALP1, the adaptor protein ASC, caspase 1 and caspase 5, and the NALP2/3 inflammasomes that contain, in addition to NALP2 or NALP3, the caspase recruitment domain (CARD)-containing protein Cardinal, ASC and caspase 1 (Figure 1). The NALPs are the central proteins in the inflammasome complex and belong to the NLR (NACHT-LRR) family of cytoplasmic proteins that also includes the NOD proteins. Fourteen NALP proteins have been identified in humans, but the role of most of these proteins remains to be determined. ASC is another essential component of the complex and connects the NALPs to caspase 1. Cardinal, a key component of the NALP2/3 inflammasome, has the same structural organisation as the carboxy-terminal region of NALP1. What does it do? The inflammasome is a molecular platform for the activation of pro-inflammatory caspases. The association of NALP and ASC via their pyrin domains (PYDs) allows the recruitment of the CARD-containing caspases 1 and 5, bringing them into close proximity and resulting in their activation. These active caspases then cleave their two known substrates, the pro-inflammatory cytokines IL-1β and IL-18. Processing leads to secretion of the active cytokines and elicits a potent inflammatory response. Where is it located? All of the inflammasome components assemble and function in the cytoplasm. Intriguingly, after activation of the inflammasome, several components, namely caspase-1, caspase-5 and ASC, are secreted along with IL-1β, although the extracellular function, if any, of these proteins is not known. How is it regulated? Little is known about the natural stimuli that lead to the assembly and activation of the inflammasome. Similar to Toll-like receptors, activation of the inflammasome is thought to occur through the recognition of pathogen-associated molecular patterns (PAMPs) by the LRRs of the NALP proteins. The only bacterial component that is currently known to activate the NALP3 inflammasome is muramyl dipeptide (MDP), a degradation product of peptidoglycan from bacterial cell walls. Excessive or uncontrolled IL-1β production is harmful to the host and is therefore tightly controlled. Several proteins such as the CARD-containing proteins COP and Iceberg, the caspase 1 inhibitor PI-9 and pyrin are thought to regulate inflammasome activity by interfering with either the recruitment of caspase 1 to the inflammasome or caspase-1 activity. Is it involved in disease? Mutations in the gene encoding NALP3, CIAS1, have been associated with several autoinflammatory disorders, such as Muckle-Wells syndrome, familial cold urticaria and CINCA (chronic infantile neurological cutaneous and articular autoinflammatory disease). These disorders are characterized by recurrent episodes of fever and serosal inflammation due to increased production of IL-1β and can be successfully treated with the natural IL-1 inhibitor IL-1ra.