title: TWEAK/Fn14 interaction promotes oxidative stress through NADPH oxidase activation in macrophages.
abstract: OBJECTIVE
  The interaction between TNF-like weak inducer of apoptosis (TWEAK, Tnfsf12) and the receptor, fibroblast growth factor-inducible 14 (Fn14), regulates vascular damage through different mechanisms, including inflammation. Oxidative stress plays a major role in inflammation and the development of atherosclerosis, but the relationship between TWEAK and oxidative stress is, however, poorly understood.
  
  
  RESULTS
  In this study, we found that TWEAK and Fn14 are co-localized with the NADPH subunits, p22phox and Nox2, in human advanced atherosclerotic plaques. Using primary human macrophages and a murine macrophage cell line, we demonstrate that TWEAK promotes ROS production and enhances NADPH oxidase activity. Hence, we show a direct involvement of the TWEAK-Fn14 axis in oxidative stress, as genetic silencing of Fn14 or Nox2 abrogates the TWEAK-induced ROS production. Furthermore, our results point at Rac1 as an upstream mediator of TWEAK during oxidative stress. Finally, using an in vivo murine model we confirmed the major role of TWEAK in oxidative stress, as genetic silencing of Tnfsf12 in an ApoE(-/-) background reduces the number of DHE and 8-hydroxydeoxyguanosine-positive macrophages by 50%.
  
  
  CONCLUSIONS
  Our results suggest that TWEAK regulates vascular damage by stimulating ROS production in an Nox2-dependent manner. These new insights into the TWEAK/Fn14 axis underline their potential use as therapeutic targets in atherosclerosis.
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Julio
authors.initials: J
authors.lastname: Madrigal-Matute
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Valvanera
authors.initials: V
authors.lastname: Fernandez-Laso
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sastre
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Llamas-Granda
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Martin-Ventura
authors.affiliation: Division of Cardiovascular Sciences, CIMA University of Navarra, Pamplona, Spain Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Zalba
authors.affiliation: Vascular Research Lab, IIS-Fundación Jiménez Díaz, Autonoma University, Av. Reyes Católicos 2, 28040 Madrid, Spain lblanco@fjd.es.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
mesh_terms: D000818:Animals; D002340:Carotid Artery Diseases / Q000378:metabolism; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004789:Enzyme Activation; D005978:Glutathione / Q000032:analysis; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000502:physiology*; D018384:Oxidative Stress; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000502:physiology
chemical_list: D000074049:Cytokine TWEAK; D018124:Receptors, Tumor Necrosis Factor; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors; D019255:NADPH Oxidases; D020830:rac1 GTP-Binding Protein; D005978:Glutathione
keywords: Atherosclerosis; Fn14; NADPH oxidase; Oxidative stress; TWEAK