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

Abstract

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.

• Authors: Julio Madrigal-Matute, Valvanera Fernandez-Laso, Cristina Sastre, Patricia Llamas-Granda, Jesús Egido, José Luis Martin-Ventura, Guillermo Zalba, Luis Miguel Blanco-Colio
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 108 Issue 1 Pg. 139-47 (Oct 01 2015) ISSN: 1755-3245 [Electronic] England
• PMID: 26224570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected].

Chemical References

• Cytokine TWEAK
• Receptors, Tumor Necrosis Factor
• TNFRSF12A protein, human
• TNFSF12 protein, human
• TWEAK Receptor
• Tnfrsf12a protein, mouse
• Tumor Necrosis Factors
• NADPH Oxidases
• rac1 GTP-Binding Protein
• Glutathione

Topics

• Animals
• Carotid Artery Diseases (metabolism)
• Cells, Cultured
• Cytokine TWEAK
• Enzyme Activation
• Glutathione (analysis)
• Humans
• Macrophages (metabolism)
• Mice
• NADPH Oxidases (physiology)
• Oxidative Stress
• Receptors, Tumor Necrosis Factor (physiology)
• TWEAK Receptor
• Tumor Necrosis Factors (physiology)
• rac1 GTP-Binding Protein (physiology)