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
Affiliations
Siân P. Cartland
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia
Scott W. Genner
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia
Gonzalo J. Martínez
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
Stacy Robertson
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia
Maaike Kockx
ANZAC Research Institute, Sydney, Australia
Ruby CY. Lin
School of Medical Sciences, University of New South Wales, Sydney, Australia
John F. O'Sullivan
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
Yen Chin Koay
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia
Pradeep Manuneedhi Cholan
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia
Melkam A. Kebede
Charles Perkins Centre, School of Life and Environmental Sciences, University of Sydney, Sydney, Australia
Andrew J. Murphy
Baker Heart and Diabetes Institute, Melbourne, Australia
Seth Masters
Walter and Elisa Hall Institute of Medical Research, Melbourne, Australia
Martin R. Bennett
Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
Wendy Jessup
ANZAC Research Institute, Sydney, Australia
Leonard Kritharides
ANZAC Research Institute, Sydney, Australia
Carolyn Geczy
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; School of Medical Sciences, University of New South Wales, Sydney, Australia
Sanjay Patel
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
Mary M. Kavurma
Heart Research Institute, 7 Eliza St, Newtown, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Corresponding author
Summary: 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. : Pathophysiology; Molecular Mechanism of Behavior; Diabetology; Immunology; Immune Response Subject Areas: Pathophysiology, Molecular Mechanism of Behavior, Diabetology, Immunology, Immune Response
