Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: Promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling

Manikandan Subramanian, Edward Thorp, Ira Tabas*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

54 Scopus citations

Abstract

RATIONALE:: Granulocyte macrophage colony-stimulating factor (GM-CSF, Csf2) is a growth factor for myeloid-lineage cells that has been implicated in the pathogenesis of atherosclerosis and other chronic inflammatory diseases. However, the role of GM-CSF in advanced atherosclerotic plaque progression, the process that gives rise to clinically dangerous plaques, is unknown. OBJECTIVE:: To understand the role of GM-CSF in advanced atherosclerotic plaque progression. METHODS AND RESULTS:: Ldlr mice and Csf2Ldlr mice were fed a Western-type diet for 12 weeks, and then parameters of advanced plaque progression in the aortic root were quantified. Lesions from the GM-CSF-deficient mice showed a substantial decrease in 2 key hallmarks of advanced atherosclerosis, lesional macrophage apoptosis and plaque necrosis, which indicates that GM-CSF promotes plaque progression. Based on a combination of in vitro and in vivo studies, we show that the mechanism involves GM-CSF-mediated production of interleukin-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell survival protein Bcl-2 (B-cell lymphoma 2) and by increasing oxidative stress. CONCLUSIONS:: In low-density lipoprotein-driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its interleukin-23-inducing activity rather than its role as a growth factor.

Original languageEnglish (US)
Pages (from-to)e13-e24
JournalCirculation research
Volume116
Issue number2
DOIs
StatePublished - Jan 16 2015

Keywords

  • apoptosis
  • atherosclerosis
  • cytokines
  • granulocyte macrophage colony-stimulating factor
  • intercellular signaling peptides and proteins
  • interleukin-23

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint

Dive into the research topics of 'Identification of a non-growth factor role for GM-CSF in advanced atherosclerosis: Promotion of macrophage apoptosis and plaque necrosis through IL-23 signaling'. Together they form a unique fingerprint.

Cite this