Identification of a Non-Growth Factor Role for GM-CSF in Advanced Atherosclerosis: Promotion of Macrophage Apoptosis and Plaque Necrosis Through IL-23 Signaling
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 Csf2-/-Ldlr-/- mice were fed a Western-type diet for 12 wks, 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 two 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 IL-23, which increases apoptosis susceptibility in macrophages by promoting proteasomal degradation of the cell-survival protein Bcl-2 and by increasing oxidative stress.
Conclusions: In LDL-driven atherosclerosis in mice, GM-CSF promotes advanced plaque progression by increasing macrophage apoptosis susceptibility. This action of GM-CSF is mediated by its IL-23-inducing activity rather than its role as a growth factor.
- Received July 10, 2014.
- Revision received October 21, 2014.
- Accepted October 27, 2014.