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

96 Citations (Scopus)

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

Fingerprint

Caspase 2
Inflammasomes
Endoplasmic Reticulum Stress
Mitochondria
Inflammation
Infection
Innate Immunity
Cellular Immunity
Leucine
Reactive Oxygen Species
Nucleotides

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

Cite this

Bronner, D. N., Abuaita, B. H., Chen, X., Fitzgerald, K. A., Nuñez, G., He, Y., ... 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

Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage. / Bronner, Denise N.; Abuaita, Basel H.; Chen, Xiaoyun; Fitzgerald, Katherine A.; Nuñez, Gabriel; He, Yongqun; Yin, Xiao-Ming; O'Riordan, Mary X D.

In: Immunity, Vol. 43, No. 3, 3151, 15.09.2015, p. 451-462.

Research output: Contribution to journalArticle

Bronner, DN, Abuaita, BH, Chen, X, Fitzgerald, KA, Nuñez, G, He, Y, Yin, X-M & O'Riordan, MXD 2015, 'Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage', Immunity, vol. 43, no. 3, 3151, pp. 451-462. https://doi.org/10.1016/j.immuni.2015.08.008
Bronner, Denise N. ; Abuaita, Basel H. ; Chen, Xiaoyun ; Fitzgerald, Katherine A. ; Nuñez, Gabriel ; He, Yongqun ; Yin, Xiao-Ming ; O'Riordan, Mary X D. / Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage. In: Immunity. 2015 ; Vol. 43, No. 3. pp. 451-462.
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