The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP
By Geun-Shik Lee, N. Subramanian, A. I. Kim, I. Aksentijevich, R. Goldbach-Mansky, D. Sacks, Ronald N. Germain, Daniel L. Kastner, J. Chae. Nature, 2012
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Mutations in the gene encoding NLRP3 cause a spectrum of autoinflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS). NLRP3 is a key component of one of several distinct cytoplasmic multiprotein complexes (inflammasomes) that mediate the maturation of the proinflammatory cytokine interleukin-1β (IL-1β) by activating caspase-1. Although several models for inflammasome activation, such as K+ efflux, generation of reactive oxygen species and lysosomal destabilization, have been proposed, the precise molecular mechanism of NLRP3 inflammasome activation, as well as the mechanism by which CAPS-associated mutations activate NLRP3, remain to be elucidated. Here we show that the murine calcium-sensing receptor (CASR) activates the NLRP3 inflammasome, mediated by increased intracellular Ca2+ and decreased cellular cyclic AMP (cAMP). Ca2+ or other CASR agonists activate the NLRP3 inflammasome in the absence of exogenous ATP, whereas knockdown of CASR reduces inflammasome activation in response to known NLRP3 activators. CASR activates the NLRP3 inflammasome through phospholipase C, which catalyses inositol-1,4,5-trisphosphate production and thereby induces release of Ca2+ from endoplasmic reticulum stores. The increased cytoplasmic Ca2+ promotes the assembly of inflammasome components, and intracellular Ca2+ is required for spontaneous inflammasome activity in cells from patients with CAPS. CASR stimulation also results in reduced intracellular cAMP, which independently activates the NLRP3 inflammasome. cAMP binds to NLRP3 directly to inhibit inflammasome assembly, and downregulation of cAMP relieves this inhibition. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is substantially lower than for wild-type NLRP3, and the uncontrolled mature IL-1β production from CAPS patients’ peripheral blood mononuclear cells is attenuated by increasing cAMP. Taken together, these findings indicate that Ca2+ and cAMP are two key molecular regulators of the NLRP3 inflammasome that have critical roles in the molecular pathogenesis of CAPS.
Subfields: Molecular Biology, Physiology, Sensory Systems
View Paper: https://www.semanticscholar.org/paper/9cec6aa2857056dbf52ae1ff07bba6b0af1e5dbd
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Citations in the corpus
- Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome. (2016, background): “See also Figure S2. mechanisms (Lee et al., 2012; Sokolowska et al., 2015; Yan et al., 2015), so we investigated the role of the cAMP-PKA pathway in LCA-induced inflammasome inhibition.”
- The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation (2019, background): “Furthermore, the inhibition of IP3R by 2-aminoethoxy diphenylborinate (2APB) prevents Ca2+ flux and NLRP3 activation [80].”
- Initiation and perpetuation of NLRP3 inflammasome activation and assembly (2015, background): “(81) also reported negative regulation of NLRP3 by adenylyl cyclase (ADCY) and its product cAMP, which was relieved by CASR-mediated Giα activation.”
- The cell biology of inflammasomes: Mechanisms of inflammasome activation and regulation (2016, background): “Production of reactive oxygen species (ROS), potassium efflux, changes in cell volume, calcium signaling, and lysosomal disruption have all been proposed as critical upstream signals required for NLRP3 activation (Cruz et al., 2007; Pétrilli et al., 2007; Cassel et al., 2008; Dostert et al., 2008; H”
- An update on the regulatory mechanisms of NLRP3 inflammasome activation (2021, background): “Calcium signaling and calcium-sensing receptor (CaSR): Intracellular Ca flux plays an essential role in the assembly and activation of the NLRP3 inflammasome induced by multiple stimuli.(104,105) Studies showed that CaSR signaling promotes NLRP3 inflammasome assembly through intracellular Ca flux an”