Novel aspects of innate immunity in human atherosclerosis and thrombosis

Atherosclerotic plaque disruption followed by thrombus formation, can lead to fatal diseases, such as myocardial infarction and stroke, when the thrombus occludes the vessel-wall. Thrombus formation does not always cause sudden occlusion but is often started days even weeks before the acute event. This thesis investigated whether inflammatory responses are involved in the process from thrombus outgrowth to occlusive lesion. The main findings are that neutrophils and neutrophil extracellular traps (NETs), hardly occurred in intact-, but were found large quantities in thrombosed plaques. Not only granulocytes but also mast cells, eosinophils and macrophages were found to release ETs, albeit to a lesser extent. The generation of ETs, marking a distinct form of cell death (etosis) increased significantly with the age of thrombus, and etosis even appeared to be the major form of cell death in the organizing thrombus. Subsets of innate lymphoid cells, a relatively new family of immune cells and not previously described in human plaques, could be identified in all developing stages of atherogenesis. Moreover, we performed a clinical-pathological follow-up study of patients who had thrombosuction in the coronaries or in the cerebral vessels. The composition and the age of the thrombus were positively correlated with the risk of mortality in patients with myocardial infarction and stroke. We postulate that thrombus age and ETs (mainly released by neutrophils) and other innate inflammatory cells can act as biomarkers for thrombus (in)stability. Furthermore, ETs and ILCs could potentially act as targets for treatment of patients with acute atherothrombotic disease.