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Immune Mechanisms of Necrotic DNA Phagocytosis by Neutrophils: A Role for Integrins

Project description

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.

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.

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Coordinator

KATHOLIEKE UNIVERSITEIT LEUVEN
Net EU contribution
€ 178 320,00
Address
Oude markt 13
3000 Leuven
Belgium

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Region
Vlaams Gewest Prov. Vlaams-Brabant Arr. Leuven
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00