TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis

Siân P. Cartland, Scott W. Genner, Gonzalo J. Martínez, Stacy Robertson, Maaike Kockx, Ruby C. Y. Lin, John F. O'Sullivan, Yen Chin Koay, Pradeep Manuneedhi Cholan, Melkam A. Kebede, Andrew J. Murphy, Seth Masters, Martin R. Bennett, Wendy Jessup, Leonard Kritharides, Carolyn Geczy, Sanjay Patel, Mary M. Kavurma*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

Original languageEnglish
Pages (from-to)41-52
Number of pages26
JournaliScience
Volume12
DOIs
Publication statusPublished - 22 Feb 2019
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • Diabetology
  • Immune Response
  • Immunology
  • Molecular Mechanism of Behavior
  • Pathophysiology

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