iScience (Feb 2019)

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

Journal volume & issue
Vol. 12
pp. 41 – 52

Abstract

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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