Critical role for calcium mobilization in activation of the NLRP3 inflammasome.
The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome mediates production of inflammatory mediators, such as IL-1β and IL-18, and as such is implicated in a variety of inflammatory processes, including infection, sepsis, autoinflammatory diseases, and metabolic diseases. The proximal steps in NLRP3 inflammasome activation are not well understood. Here we elucidate a critical role for Ca(2+) mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca(2+) mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca(2+) signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca(2+) release from the endoplasmic reticulum, amplifies NLRP3 inflammasome activation, thus linking endoplasmic reticulum stress to activation of the NLRP3 inflammasome. Our findings support a model for NLRP3 inflammasome activation by Ca(2+)-mediated mitochondrial damage.
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Tomohiko
T
Murakami
Johan
J
Ockinger
Jiujiu
J
Yu
Vanessa
V
Byles
Aisleen
A
McColl
Aldebaran M
AM
Hofer
Tiffany
T
Horng
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005434:Flow Cytometry / Q000379:methods; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction
D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D000255:Adenosine Triphosphate; D002118:Calcium