title: Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS).
abstract: Reactive oxygen species (ROS) have an established role in inflammation and host defense, as they kill intracellular bacteria and have been shown to activate the NLRP3 inflammasome. Here, we find that ROS generated by mitochondrial respiration are important for normal lipopolysaccharide (LPS)-driven production of several proinflammatory cytokines and for the enhanced responsiveness to LPS seen in cells from patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), an autoinflammatory disorder caused by missense mutations in the type 1 TNF receptor (TNFR1). We find elevated baseline ROS in both mouse embryonic fibroblasts and human immune cells harboring TRAPS-associated TNFR1 mutations. A variety of antioxidants dampen LPS-induced MAPK phosphorylation and inflammatory cytokine production. However, gp91(phox) and p22(phox) reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits are dispensable for inflammatory cytokine production, indicating that NADPH oxidases are not the source of proinflammatory ROS. TNFR1 mutant cells exhibit altered mitochondrial function with enhanced oxidative capacity and mitochondrial ROS generation, and pharmacological blockade of mitochondrial ROS efficiently reduces inflammatory cytokine production after LPS stimulation in cells from TRAPS patients and healthy controls. These findings suggest that mitochondrial ROS may be a novel therapeutic target for TRAPS and other inflammatory diseases.
authors.affiliation: Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutesof Health, Bethesda, MD 20892, USA.
authors.forename: Ariel C
authors.initials: AC
authors.lastname: Bulua
authors.forename: Anna
authors.initials: A
authors.lastname: Simon
authors.forename: Ravikanth
authors.initials: R
authors.lastname: Maddipati
authors.forename: Martin
authors.initials: M
authors.lastname: Pelletier
authors.forename: Heiyoung
authors.initials: H
authors.lastname: Park
authors.forename: Kye-Young
authors.initials: KY
authors.lastname: Kim
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D016207:Cytokines / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000503:physiopathology; D015850:Interleukin-6 / Q000276:immunology / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000276:immunology / Q000502:physiology; D009154:Mutation; D009569:Nitric Oxide / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D009569:Nitric Oxide; D020929:Mitogen-Activated Protein Kinase Kinases