Critical role for calcium mobilization in activation of the NLRP3 inflammasome

Tomohiko Murakami, Johan Ockinger, Jiujiu Yu, Vanessa Byles, Aisleen McColl, Aldebaran M. Hofer, Tiffany Horng

Research output: Contribution to journalArticle

283 Citations (Scopus)

Abstract

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 Ca2+mobilization in activation of the NLRP3 inflammasome by multiple stimuli. We demonstrate that blocking Ca2+ mobilization inhibits assembly and activation of the NLRP3 inflammasome complex, and that during ATP stimulation Ca2+ signaling is pivotal in promoting mitochondrial damage. C/EPB homologous protein, a transcription factor that can modulate Ca2+ 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 Ca2+-mediated mitochondrial damage.

Original languageEnglish (US)
Pages (from-to)11282-11287
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number28
DOIs
StatePublished - Jul 10 2012

Fingerprint

Inflammasomes
Calcium
Interleukin-18
Endoplasmic Reticulum Stress
Metabolic Diseases
Interleukin-1
Leucine
Endoplasmic Reticulum
Sepsis
Transcription Factors
Nucleotides
Adenosine Triphosphate
Infection

Keywords

  • Innate immunity
  • Mitochondria

ASJC Scopus subject areas

  • General

Cite this

Critical role for calcium mobilization in activation of the NLRP3 inflammasome. / Murakami, Tomohiko; Ockinger, Johan; Yu, Jiujiu; Byles, Vanessa; McColl, Aisleen; Hofer, Aldebaran M.; Horng, Tiffany.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 28, 10.07.2012, p. 11282-11287.

Research output: Contribution to journalArticle

Murakami, Tomohiko ; Ockinger, Johan ; Yu, Jiujiu ; Byles, Vanessa ; McColl, Aisleen ; Hofer, Aldebaran M. ; Horng, Tiffany. / Critical role for calcium mobilization in activation of the NLRP3 inflammasome. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 28. pp. 11282-11287.
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