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 Cy 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

doi:10.1016/j.isci.2018.12.037

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

iScience. 2019 Feb 22:12:41-52. doi: 10.1016/j.isci.2018.12.037. Epub 2019 Jan 4.

Authors

Siân P Cartland¹, Scott W Genner², Gonzalo J Martínez³, Stacy Robertson¹, Maaike Kockx⁴, Ruby Cy Lin⁵, John F O'Sullivan⁶, Yen Chin Koay¹, Pradeep Manuneedhi Cholan¹, Melkam A Kebede⁷, Andrew J Murphy⁸, Seth Masters⁹, Martin R Bennett¹⁰, Wendy Jessup⁴, Leonard Kritharides⁴, Carolyn Geczy¹¹, Sanjay Patel⁶, Mary M Kavurma¹²

Affiliations

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.

Grants and funding

RG/13/14/30314/BHF_/British Heart Foundation/United Kingdom