Activation by calcium

Several models of inflammasome activation, such as K⁺ efflux, generation of reactive oxygen species and lysosomal destabilization, have been proposed. In Nature, Chae and colleagues show that recognition of extracellular Ca²⁺ through the calcium-sensing receptor CASR activates the NLRP3 inflammasome. CASR activates phospholipase C, which catalyzes the production of inositol-1,4,5-triphosphate and release of Ca²⁺ from endoplasmic reticulum stores. A greater abundance of cytoplasmic Ca²⁺ promotes assembly of components of the NLRP3 inflammasome. Stimulation via CASR also diminishes the abundance of intracellular cAMP, which binds NLRP3 directly to inhibit inflammasome assembly. Thus, downregulation of cAMP relieves this inhibition. Mutant NLRP3 from patients with cryopyrin-associated periodic syndrome binds cAMP with lower affinity than does wild-type NLRP3. Increasing cAMP attenuates the uncontrolled production of interleukin 1β by peripheral blood mononuclear cells in such patients. These results suggest that extracellular Ca²⁺ can function as a danger signal.

Nature (11 November 2012) doi:10.1038/nature11588