Background: Atherosclerosis is promoted by different risk factors, for example advanced glycation end products (AGEs), oxidized phospholipids and mechanical strain. Various cytokines such as interleukin (IL)-33, a strong activator of endothelial cells (ECs), also play a role in this disease. Neuronal guidance cues are essential in the development of the nervous system but are also involved in atherosclerosis. For example, netrin-1 inhibits macrophage emigration from the plaques and stimulates smooth muscle cell (SMC) migration into the intima of the vessel wall. Granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) have a chemotactic effect on monocytes and promote survival and activation of macrophages in atherosclerotic lesions.
Methods and results: IL-33 stimulated the expression of netrin-1 and semaphorin-3A in human ECs through NF-kappaB, like for the upregulation of GM-CSF and M-CSF production. In contrast to the induction of CSF expression, this effect was only partially independent of IL-1. The 3-hydroxy-3-methylglutaryl-CoenzymeA (HMG-CoA) reductase inhibitor fluvastatin inhibited the increase in M-CSF but not in GM-CSF, netrin-1 and semaphorin-3A expression. IL-33, IL-1beta, netrin-1, semaphorin-3A, GM-CSF and M-CSF protein were detected in ECs from human atherosclerotic plaques by immunofluorescence analysis. AGEs, oxidized phospholipids and mechanical strain showed no influence on IL-33 expression.
Conclusion: Through stimulation of neuronal guidance cue expression with subsequent retention of macrophages and migration of SMCs to the intima, IL-33 may promote chronic inflammation and disease progression within atherosclerotic lesions. CSF upregulation by IL-33 may further enhance the inflammatory process by recruiting additional monocytes and promoting activation and survival of plaque macrophages.