Emerging Activators and Regulators of Inflammasomes and Pyroptosis

The inflammasome is a cytosolic immune signaling complex that induces inflammation and pyroptosis. Inflammasome complexes respond to a variety of pathogens, as well as danger or homeostasis-altering signals; they can play critical roles in the development of autoinflammatory conditions and cancer. Studies have now provided additional insights into the activation mechanisms and regulation of established inflammasome complexes, including NLRP1b, NLRP3, NOD-like receptor family apoptosis inhibitory protein (NAIP)–NLRC4, absent in melanoma (AIM)2, caspase-11, and pyrin. New activators and regulators of emerging NLRP6 and NLRP9b inflammasome complexes have also been described. We highlight the latest progress in our understanding of the molecular mechanisms governing inflammasome activation and pyroptosis, including the discovery of the pore-forming protein gasdermin D (GSDMD). We also discuss the importance of inflammasome activators and regulators in health and disease. The inflammasome family is expanding and now includes the canonical AIM2, NAIP-NLRC4, NLRP1, NLRP3, NLRP6, NLRP9b, and pyrin inflammasomes and the noncanonical caspase-11 inflammasome.Inflammasome sensors detect a growing constellation of pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and homeostasis-altering molecular processes (HAMPs).Activation of human caspase-1, -4, and -5, or mouse caspase-1 and -11, induces cleavage of the pore-forming protein GSDMD, mediating pyroptosis.Assembly and signaling of the inflammasome often requires transcriptional and translational regulation, and spatial localization of inflammasome components at the site of organelles, such as the Golgi and mitochondria.Targeting inflammasome components has potential therapeutic value in the treatment of certain infections, cancers, and inflammatory conditions.