Abstract

Epigenetic Enzymes Regulating Macrophage Function and Inflammatory Responses

Menno de Winther, Professor, University Of Amsterdam

Inflammation plays a prominent role in chronic inflammatory diseases, such as atherosclerosis development and associated cardiovascular disease. Macrophages are key immune cells found in atherosclerotic plaques and critically shape disease development and clinical outcome. In response to micro-environmental stimuli they adopt different activation states driving their functional repertoire. A main focus of our research interest is on the targeting of macrophage regulation, to allow skewing of their phenotype and improve disease outcome. Epigenetic pathways, including histone modifications, are now emerging as important regulators of immune responses. In recent studies we have identified histone-modifying enzymes that are regulated in human atherosclerotic plaque stability and affect macrophage functioning. We could show that modifying the epigenome, by for instance targeting of HDAC3, can be used to beneficially influence the phenotype of macrophages, to allow dampening of atherosclerosis development and stabilize atherosclerotic lesions. Additional enzymes have been identified by us and are being studied in relation to atherosclerosis and other inflammatory diseases. Overall, approaches targeting epigenetic pathways to adapt the functional repertoire of macrophages may hold novel approaches for future management of inflammatory diseases.