Document Detail

The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP.
MedLine Citation:
PMID:  23143333     Owner:  NLM     Status:  MEDLINE    
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 Ca(2+) and decreased cellular cyclic AMP (cAMP). Ca(2+) 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 Ca(2+) from endoplasmic reticulum stores. The increased cytoplasmic Ca(2+) promotes the assembly of inflammasome components, and intracellular Ca(2+) 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 Ca(2+) and cAMP are two key molecular regulators of the NLRP3 inflammasome that have critical roles in the molecular pathogenesis of CAPS.
Geun-Shik Lee; Naeha Subramanian; Andrew I Kim; Ivona Aksentijevich; Raphaela Goldbach-Mansky; David B Sacks; Ronald N Germain; Daniel L Kastner; Jae Jin Chae
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural     Date:  2012-11-11
Journal Detail:
Title:  Nature     Volume:  492     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-11     Completed Date:  2013-02-05     Revised Date:  2014-10-14    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  123-7     Citation Subset:  IM    
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MeSH Terms
Adenosine Triphosphate / metabolism
Calcium / metabolism*
Calcium Signaling*
Carrier Proteins / genetics,  metabolism*
Cryopyrin-Associated Periodic Syndromes / etiology,  genetics,  metabolism
Cyclic AMP / metabolism*
Endoplasmic Reticulum / metabolism
Gene Knockdown Techniques
Inflammasomes / metabolism*
Inositol 1,4,5-Trisphosphate / metabolism
Interleukin-1beta / biosynthesis,  metabolism
Leukocytes, Mononuclear / metabolism
Protein Binding
Receptors, Calcium-Sensing / metabolism*
Receptors, G-Protein-Coupled / metabolism*
Type C Phospholipases / metabolism
Grant Support
Reg. No./Substance:
0/CASR protein, mouse; 0/CIAS1 protein, mouse; 0/Carrier Proteins; 0/Inflammasomes; 0/Interleukin-1beta; 0/Receptors, Calcium-Sensing; 0/Receptors, G-Protein-Coupled; 85166-31-0/Inositol 1,4,5-Trisphosphate; 8L70Q75FXE/Adenosine Triphosphate; E0399OZS9N/Cyclic AMP; EC 3.1.4.-/Type C Phospholipases; SY7Q814VUP/Calcium
Comment In:
Nat Rev Immunol. 2013 Jan;13(1):1   [PMID:  23197112 ]

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