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

Cartland, S. P. et al. (2019) TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis. iScience, 12, pp. 41-52. (doi: 10.1016/j.isci.2018.12.037) (PMID:30665196) (PMCID:PMC6348195)

Abstract

Circulating 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 coronary artery disease patients 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, 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.

• Item Type: Articles
• Additional Information: This work was supported by Heart Foundation of Australia Career Development Award (CR 12S 6833; MMK), Sydney University Early Career Research Grant (SPC) and Sydney Medical School Foundation Fellowship (JO).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Robertson, Dr Stacy
• Authors: Cartland, S. P., Genner, S. W., Martínez, G. J., Robertson, S., Kockx, M., Lin, R. C., O'Sullivan, J. F., Koay, Y. C., Cholan, P. M., Kebede, M. A., Murphy, A. J., Masters, S., Bennett, M. R., Jessup, W., Kritharides, L., Geczy, C., Patel, S., and Kavurma, M. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: iScience
• Publisher: Elsevier (Cell Press)
• ISSN: 2589-0042
• ISSN (Online): 2589-0042
• Published Online: 04 January 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in iScience 12: 41-52
• Publisher Policy: Reproduced under a Creative Commons License