Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation

Abstract

Hosts have evolved strategies to detect and respond rapidly to invading microorganisms and host-cell damage or 'danger signals'. The caspase-1 inflammasome is a dynamic complex in which specific NOD-like receptors (NLRs) and adaptor molecules are brought into play, depending on the nature of the primary trigger. ASC (apoptosis-associated speck-like protein containing a CARD) has a central role in the inflammasome. Through homotypic protein–protein interactions with its own CARD (caspase-recruitment domain) and PYD (pyrin domain), ASC is thought to act as a direct bridge between the sensor NALPs (NACHT-, LRR- and pyrin-domain-containing proteins) and the downstream effector caspase-1. The two-signal activation model is derived from studies of the treatment of cultured macrophages with pathogen-associated molecular patterns, which, in the absence of ATP, are insufficient to activate the inflammasome complex. However, infection with bacterial pathogens both in vitro and in vivo does not require ATP to trigger the inflammasome. NALP3 is involved in sensing toxins, 'danger signals' such as gout crystals, Staphylococcus aureus, Listeria monocytogenes, bacterial RNA and trinitrophenylchloride. IPAF (ICE-protease activating factor) is involved in sensing various intracellular bacterial pathogens, such as Salmonella typhimurium, Shigella flexneri and Legionella pneumophila. Flagellin might be one common pathogen-associated molecule that is recognized by IPAF and/or NAIP5 (neuronal apoptosis inhibitor protein 5). ASC is required for the inflammasome recognition of Francisella tularensis.