The IL-33/ST2 pathway, inflammation and atherosclerosis: Trigger and target?

The “inflammatory hypothesis” of atherosclerosis postulates that inflammatory cell signalling drives the formation, growth and ultimately the instability of atherosclerotic plaques, setting up the substrate for the thrombotic response that causes myocardial damage or infarction. The recent Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial has been hailed as the first demonstration, ex iuvantibus, of the inflammatory hypothesis. Indeed, interleukin (IL)-1β inhibition was found to reduce cardiovascular events in patients with previous myocardial infarction and raised high-sensitivity C-reactive protein, despite no effects on the lipid profile. These results prompt a dissection of inflammatory mechanisms of atherosclerosis in order to search for specific biomarkers with prognostic value and/or therapeutic targets. Under this respect, the IL-33/suppression of tumorigenesis 2 (ST2) pathway deserves consideration. Indeed, its elements are particularly expressed in the endothelium of arterial vessels, and the interaction between IL-33 and the ST2 receptor blunts the immune response characteristic of atherosclerosis. By contrast, soluble ST2 (sST2) acts as a decoy receptor for IL-33, thus blocking its protective effects. Despite a solid theoretical framework, no definite demonstration of an involvement of the IL-33/ST2 pathway in atherosclerosis has been provided. Therefore, further studies are warranted to verify if elements of the IL-33/ST2 pathway may be proposed as markers of plaque burden and predictors of future cardiovascular events, and to explore the potential clinical benefit of enhanced IL-33/ST2 signalling in atherosclerosis.