TWEAK/Fn14 interaction promotes oxidative stress through NADPH oxidase activation in macrophages

Julio Madrigal-Matute, Valvanera Fernandez-Laso, Cristina Sastre, Patricia Llamas-Granda, Jesús Egido, José Luis Martin-Ventura, Guillermo Zalba, Luis Miguel Blanco-Colio

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Aim 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. Methods and 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.

Original languageEnglish (US)
Pages (from-to)139-147
Number of pages9
JournalCardiovascular research
Issue number1
StatePublished - May 21 2015
Externally publishedYes


  • Atherosclerosis
  • Fn14
  • NADPH oxidase
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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