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Immunity. 2015 Sep 15;43(3):451-62. doi: 10.1016/j.immuni.2015.08.008. Epub 2015 Sep 1.

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

Author information

1
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
2
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
3
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
4
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109 USA.
5
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109 USA; Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 USA.
6
Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109 USA. Electronic address: oriordan@umich.edu.

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.

PMID:
26341399
PMCID:
PMC4582788
DOI:
10.1016/j.immuni.2015.08.008
[Indexed for MEDLINE]
Free PMC Article

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