Impact of plasminogen binding on innate immune cell function

Content Monocytes and macrophages are white blood cells (leukocytes), which can remove pathogens and therefore are essential in immune responses however, they are also crucially involved atherosclerotic lesion development of blood vessels. An important feature of these cells is to migrate towards an inflammatory site. This process and their activation can be influenced by the binding of plasminogen, which also supports its activation to plasmin. The main function of plasmin is to break down blood clots, but also facilitates migration of immune cells. Only recently, a novel plasminogen receptor, Plg-RKT was discovered, which essentially mediates leukocyte migration. However, the detailed consequences of Plg-RKT-mediated leukocyte function during atherosclerosis have not been addressed yet. Hence, we want to investigate the effects of this plasminogen receptor in atherosclerosis. Hypothesis We aim to elucidate the role of Plg-R KT in different stages of atherosclerotic disease. Based on our previous data, we hypothesize, that Plg-R KT deficiency will decrease macrophage and foam cell accumulation in developing plaques, accompanied by elevated collagen deposition supporting plaque stability. Thus, we assume that lack of Plg-RKT will reduce plaque development and progression, however in contrast can ameliorate plaque regression. Due to atherosclerotic vessel occlusion collateral vessels can be formed, which is enhanced by immune cell accumulation. Hence, we expect that this process is positive influenced by the presence of Plg-RKT. To better understand the underlying mechanisms behind the function of Plg-RKT, we plan to characterize Plg-RKT-deficient and wild-type macrophages in cell culture. As our preliminary data demonstrate that monocytes of female individuals express higher levels of Plg-RKT, we aim to elucidate gender-related differences due to Plg-R KT in atherosclerosis. Methods To address these hypotheses, we will evaluate and combine the results obtained from cell culture, animal studies and patient samples. What is new We suggest that the plasminogen receptor Plg-RKT is an important modulator of innate immune cell function. We will test our hypothesis in clinically relevant atherosclerosis models and compare data obtained in mice with results obtained in human patients. Our translational research approach will help us deepen our understanding of macrophage biology in atherosclerosis.