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iScience. 2019 Jan 4;12:41-52. doi: 10.1016/j.isci.2018.12.037. [Epub ahead of print]

TRAIL-Expressing Monocyte/Macrophages Are Critical for Reducing Inflammation and Atherosclerosis.

Author information

1
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia.
2
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia.
3
Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia; División de Enfermedades Cardiovasculares, Pontificia Universidad Católica de Chile, Santiago, Chile.
4
ANZAC Research Institute, Sydney, Australia.
5
School of Medical Sciences, University of New South Wales, Sydney, Australia.
6
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.
7
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia.
8
Baker Heart and Diabetes Institute, Melbourne, Australia.
9
Walter and Elisa Hall Institute of Medical Research, Melbourne, Australia.
10
Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.
11
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia.
12
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia. Electronic address: mary.kavurma@hri.org.au.

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.

KEYWORDS:

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

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