Activation and regulation of the inflammasomes

Abstract

For the known inflammasomes, new cofactors such as caspase 11 and the NAIPs (NLR family, apoptosis inhibitory proteins) have been described. In addition, inflammasome-independent pathways for the processing of interleukin-1β (IL-1β), such as caspase 8 activation, have recently been described. Cell-extrinsic signalling can regulate inflammasome activation. Signalling by pattern recognition or cytokine receptors primes the cell and induces NLRP3 (NOD-, LRR- and pyrin domain-containing 3) and pro-IL-1β expression, whereas signalling by type I interferons and activated T cells reduces inflammasome activation. Energy levels, mitochondrial health and lysosomal compartmentalization are constantly under the surveillance of cellular health sensors such as the apoptosome and inflammasomes. These signalling platforms detect changes in cellular homeostasis and share many structural and functional similarities. NLRP3 is strongly regulated by fluxes of K⁺, Cl⁻ and Ca²⁺. In addition, reactive oxygen species, autophagy and endoplasmic reticulum stress are important modulators of NLRP3 activity. The inflammasomes are regulated by pyrin domain- or CARD (caspase activation and recruitment domain)-only proteins, which sequester the signalling molecules. Other proteins that are known to regulate apoptosis also have a role in inflammasome signalling. Understanding the regulatory mechanisms of inflammasome activation will facilitate the development of new classes of drugs that target the inflammasomes.