Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage

Denise N. Bronner, Basel H. Abuaita, Xiaoyun Chen, Katherine A. Fitzgerald, Gabriel Nuñez, Yongqun He, Xiao Ming Yin, Mary X.D. O'Riordan

Research output: Contribution to journalArticle

141 Scopus citations

Abstract

Endoplasmic reticulum (ER) stress is observed in many human diseases, often associated with inflammation. ER stress can trigger inflammation through nucleotide-binding domain and leucine-rich repeat containing (NLRP3) inflammasome, which might stimulate inflammasome formation by association with damaged mitochondria. How ER stress triggers mitochondrial dysfunction and inflammasome activation is ill defined. Here we have used an infection model to show that the IRE1α ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1α activation increased mitochondrial reactive oxygen species, promoting NLRP3 association with mitochondria. NLRP3 was required for ER stress-induced cleavage of caspase-2 and the pro-apoptotic factor, Bid, leading to subsequent release of mitochondrial contents. Caspase-2 and Bid were necessary for activation of the canonical inflammasome by infection-associated or general ER stress. These data identify an NLRP3-caspase-2-dependent mechanism that relays ER stress to the mitochondria to promote inflammation, integrating cellular stress and innate immunity.

Original languageEnglish (US)
Article number3151
Pages (from-to)451-462
Number of pages12
JournalImmunity
Volume43
Issue number3
DOIs
StatePublished - Sep 15 2015

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Bronner, D. N., Abuaita, B. H., Chen, X., Fitzgerald, K. A., Nuñez, G., He, Y., Yin, X. M., & O'Riordan, M. X. D. (2015). Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage. Immunity, 43(3), 451-462. [3151]. https://doi.org/10.1016/j.immuni.2015.08.008