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Investigation of the role of CXCL5/CXCR1 pathway in atherosclerosis

Final Report Summary - ATHEROCHEMOKINE (Investigation of the role of CXCL5 / CXCR1 pathway in atherosclerosis)

Cardiovascular diseases (CVD) are currently the leading cause of death in developed countries. The World Health Organisation (WHO) has estimated that CVD is currently the predominant health problem worldwide (see http://www.who.int/cardiovascular_diseases/en/ online for further details) and atherosclerosis constitutes a major contributor to this growing burden of CVD. Atherosclerosis is a disease in which chronic inflammation plays a fundamental role. Indeed, inflammatory circulating cells also called white blood cells or leucocytes penetrate the arterial vessel wall and participate in the development of the atherosclerotic plaques. This phenomenon might eventually lead to thrombotic complications (occlusion of the vessel) that culminate in acute myocardial infarction (heart attack) or stroke.

Chemokines, molecules that are known to attract monocyte / macrophage (the main subset of leucocytes found in atherosclerotic plaques) from the circulation and activate them in the site of inflammation, are implicated in all stages of atherosclerosis and as such have been proposed as potential therapeutic targets. We discovered that one particular chemokine, namely CXCL5 is present in these atherosclerotic plaques and plays a protective role. This chemokine was known for a long time, but has been mainly described as a key player in acute phase of inflammation (for instance during bacterial infection) acting on another subset of leucocytes (i.e. neutrophil).

Our findings reveal an important new function for CXCL5 on macrophages in atherosclerosis. Specifically, our results demonstrate that CXCL5 is induced in atherosclerosis as the disease progresses but is not associated with neutrophil infiltration as would be expected. Instead CXCL5 has a protective role in this inflammatory context by directly acting on macrophages and controlling foam cell formation. As mentioned above, macrophages are known to enter the arterial vessel wall and participate in the development of the atherosclerotic plaques. Once there, they are able to engulf cholesterol and lipids. These lipid-loaded cells are called macrophage foam cells, which eventually die inside the atherosclerotic plaques and trigger acute thrombotic vascular disease, including myocardial infarction, stroke, and sudden cardiac death. Therefore reducing the cholesterol content of the macrophages would help to protect against myocardial infarct or stroke. The frontline therapy for atheromatous disease often involves treatment with statin and / or aspirin. Recent data indicate that part of the clinical benefits of statin and aspirin occur because of an anti-inflammatory effect that is not related to reduction of cholesterol and platelet aggregation. Whilst statin and aspirin are rather generic anti-inflammatory agents it is likely that more selective inhibitors of foam cells formation would prove beneficial in preventing and treating acute myocardial infarct and stroke. We believe that CXCL5 plays an important role in controlling macrophage foam cells formation in atherosclerosis. In concrete terms, these findings may be instrumental in paving the way towards more specific treatments for atherosclerosis.