Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage
Department of Medicine, Division of Infectious Diseases and Immunology
Animals; BH3 Interacting Domain Death Agonist Protein; Blotting, Western; Brucella abortus; Carrier Proteins; Caspase 2; Cells, Cultured; DNA-Binding Proteins; Endoplasmic Reticulum Stress; Endoribonucleases; HEK293 Cells; Host-Pathogen Interactions; Humans; Inflammasomes; Interleukin-1beta; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Protein-Serine-Threonine Kinases; RNA Interference; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors
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 IRE1alpha ER stress sensor regulates regulated mitochondrial dysfunction through an NLRP3-mediated feed-forward loop, independently of ASC. IRE1alpha 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.
DOI of Published Version
Immunity. 2015 Sep 15;43(3):451-62. doi: 10.1016/j.immuni.2015.08.008. Epub 2015 Sep 1. Link to article on publisher's site
Bronner, Denise N.; Abuaita, Basel H.; Chen, Xiaoyun; Fitzgerald, Katherine A.; Nunez, Gabriel; He, Yongqun; Yin, Xiao-Ming; and O'Riordan, Mary X. D, "Endoplasmic Reticulum Stress Activates the Inflammasome via NLRP3- and Caspase-2-Driven Mitochondrial Damage" (2015). University of Massachusetts Medical School Faculty Publications. 930.