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Not growth but death: GM-CSF/IL-23 axis drives atherosclerotic plaque vulnerability by enhancing macrophage and DC apoptosis.

Cardiovascular diseases mainly caused by atherosclerosis lead death statistics in Western societies. Atherosclerosis, a chronic inflammation of the vessel wall, is most likely initiated by endothelial dysfunction followed by a constant influx of mononuclear immune cells into the intimal layer. The latter fosters growth of atherosclerotic plaques leading to vessel narrowing and occlusion. Rupture of atherosclerotic lesions can cause myocardial infarction and stroke.1 Myeloid cells, especially macrophages and their secretion products, are known to play an important role in the pathophysiology of atherosclerosis; however, some mediators exert multiple roles and might have to be revisited. In this context, Subramanian et al2 revealed that the hematopoietic growth factor granulocyte macrophage colony-stimulating factor (GM-CSF; gene name Csf2 ), to date mostly known for its role in myeloid cell development, plays a crucial role in controlling macrophage apoptosis by induction of interleukin (IL)-23 production (Figure).



Figure. 
Granulocyte macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)-23 axis controls macrophage and dendritic cell (DC) susceptibility to apoptosis thereby influencing plaque stability. Atherosclerosis, initiated by endothelial dysfunction, is the most important underlying cause for vessel narrowing and occlusion. However not only plaque size but also plaque stability matter. This study by Subramanian et al2 highlights an important novel role for GM-CSF by inducing lesional IL-23 production (I, left ). In turn, IL-23 together with, eg, oxidized low-density lipoprotein (oxLDL) increases the susceptibility for apoptosis in plaque macrophages and DCs (II) and triggers Th1 and Th17 responses, as well as the release of reactive oxygen species (ROS; III). All of the latter increases necrotic core formation and enhances plaque vulnerability. In case of GM-CSF deficiency ( right ), lesional IL-23 levels are reduced (I) resulting in diminished myeloid cell apoptosis (reduced Mkp-1, but increased Bcl-2 expression, II), a less pronounced Th1 and Th17 profile and a decrease in lesional ROS (III). …