Project description DEENESFRITPL Role of neutrophils in the removal of necrotic DNA debris The human body loses billions of cells a day due to the cell death process known as necrosis. Improper removal of cellular debris, such as DNA, is linked to conditions such as systemic lupus erythematosus, acute liver injury, atherosclerosis and severe trauma. Neutrophils, a subset of phagocytes, are good candidates for debris removal, but the mechanisms of necrotic DNA removal are currently unknown. The main objective of the EU-funded IMPACT project is to understand how neutrophils phagocytose and eliminate necrotic DNA debris.The project will test the hypothesis that neutrophils use complement receptors to bind and phagocytose complement-coated necrotic DNA. Show the project objective Hide the project objective Objective Cell death is inherently connected to the existence of multicellular organisms. Our body loses billions of cells a day due to thermal, mechanical or chemical damage in a cell death process with loss of plasma membrane integrity and pro-inflammatory properties known as necrosis. Organisms face necrosis frequently, thus, there must be specific pathways to remove the large amount of cellular debris left behind. In this way, it is no surprise that improper removal of cellular debris, such as DNA, is associated to inflammatory diseases as lupus erythematosus, acute liver injury, atherosclerosis and severe trauma. Removal of necrotic debris is thought to be mediated by phagocytes, although reports showing it are scarce. Neutrophils, a subset of phagocytes, are good candidates for debris removal since they are abundant and quickly recruited to necrotic sites. The means used by neutrophils to identify, internalize and degrade necrotic DNA are currently unknown, thus, the main objective of my project is to understand how neutrophils phagocytose and eliminate necrotic DNA debris. Neutrophils express the DNA-sensing receptor TLR9, which is not a phagocytic receptor. However, they also express very high levels of beta2 integrins such as CD11b/CD18, which act as adhesion molecule and as complement receptor (CR3). The release of necrotic DNA promotes complement activation in vivo through several pathways, therefore, my hypothesis is that neutrophils use beta2 integrins to bind and phagocytose complement-coated necrotic DNA. To assess the role of beta2 integrins, TLR9 and complement in phagocytosis of necrotic DNA by neutrophils, I will combine a novel in vitro method (DNA deposit in coverslip) with an in vivo approach (confocal intravital microscopy). I will also develop novel peptides for DNA labelling and modulation of phagocytosis, which I will use in both models. The findings of this project will directly favor the development of novel therapies for inflammatory diseases. Fields of science medical and health scienceshealth sciencesinflammatory diseasesnatural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesmedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosisnatural sciencesphysical sciencesopticsmicroscopy Keywords Neutrophil phagocytosis DNA necrotic debris integrins complement receptor liver necrosis inflammation intravital microscopy Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2018 - Individual Fellowships Call for proposal H2020-MSCA-IF-2018 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator KATHOLIEKE UNIVERSITEIT LEUVEN Net EU contribution € 178 320,00 Address OUDE MARKT 13 3000 Leuven Belgium See on map Region Vlaams Gewest Prov. Vlaams-Brabant Arr. Leuven Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 178 320,00
