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.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Madrigal-Matute J,Fernandez-Laso V,Sastre C,Llamas-Granda P,Egido J,Martin-Ventura JL,Zalba G,Blanco-Colio LM

doi

10.1093/cvr/cvv204

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

139-47

issue

1

eissn

0008-6363

issn

1755-3245

pii

cvv204

journal_volume

108

pub_type

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