Resolution of inflammation in atherosclerosis

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Atherosclerosis, a chronic inflammation of the arterial wall, is the underlying pathomechanism for stroke and myocardial infarction. We have recently shown that neutrophils infiltrate large arteries during early and late stages of atherosclerosis and that neutropenia reduces sizes of atherosclerotic lesions. Mechanistically, neutrophils instruct inflammatory processes through release of pre-formed granule proteins or reactive oxygen species (ROS). However, as neutrophils are short-lived cells, immune-modulatory properties of apoptotic neutrophils stand out as important regulatory mechanisms in atherosclerosis. Leukocyte apoptosis occurs throughout all stages of atherosclerosis and other investigators have focused on macrophages as the source of apoptotic cells. While apoptosis in early stages of atherosclerosis is considered beneficial, it is fatal at later stages as mechanisms of apoptotic cell clearance are impaired and hence apoptotic cells undergo secondary necrosis. Here, the applicant hypothesizes that besides macrophages and smooth muscle cells neutrophils are a major source of apoptotic cells in atherosclerosis and specific interference with signaling pathways of neutrophil apoptosis, mechanisms of neutrophil clearance, and stimulation of resolution signals released upon neutrophil clearance will open new therapeutic avenues for treatment of atherosclerosis.In this proposal the applicant plans to map the prevalence of neutrophil apoptosis at various stages of human and murine atherosclerosis. Thereafter, the applicant will address the stage-dependent contribution of neutrophil apoptosis to atherosclerosis using adoptive transfer strategies and mice with altered neutrophil apoptosis rates. Finally, the applicant will specifically interfere with neutrophil apoptosis and clearance to stimulate plaque regression at early stages and plaque stabilization at later stages. During early stages, neutrophil apoptosis is increased through interference with signaling pathways that stimulate Nf-KB or inhibit ROS. Enhanced neutrophil apoptosis shall stimulate endogenous resolution mechanisms and therewith regression of atherosclerosis. Interference at later stages is designed to reduce continued arterial leukocyte infiltration, stimulate neutrophil clearance and resolution of inflammatory processes ultimately promoting plaque stabilization.