AC REMOVAL MECHANISM

Molecular and cellular mechanisms in phagocytosis of apoptotic cells

 Partecipanti

Mappa

 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

 Obiettivo del progetto (Objective)

'The proper elimination of unwanted or aberrant cells through apoptosis and subsequent phagocytosis plays a crucial role in metazoan development and tissue homeostasis. Inefficient or defective removal of apoptotic cells leads to inflammation and autoimmune diseases. Given that in vertebrates phagocytosis is a complex and highly redundant process, we are using the Drosophila model, which permits comprehensive in vivo studies and provides complement to medical and applied approaches in the field. We previously identified and characterized a novel phagocytic receptor, named Six Microns Under (Simu), which strongly binds to apoptotic cells and is required for their recognition and engulfment by glia in the nervous system and by macrophages elsewhere. However, the mode of SIMU’s action is, like of many other phagocytic receptors, still unknown. The goal of the proposed research is to elucidate the molecular and cellular mechanisms underlying the recognition of apoptotic cells by phagocytes and subsequent signaling for engulfment. We will further characterize SIMU’s function by finding its physical interaction partners, both its ligand on the apoptotic cell and its presumptive co-receptor on the phagocyte. Then we will focus on the mechanisms of their action and interaction. Based on two independent genetic screens we will test candidates with presumed or known function in phagocytosis in order to explore novel pathways in apoptotic cell clearance. By studying factors involved in different pathways we will address the redundancy issue in the phagocytosis process. Accomplishment of our research goal will shed light on the general mechanisms of receptor binding, clustering and signaling in phagocytosis, which will provide novel and important insight into a key biological process with potential translation into equivalent studies in mammalian systems and medical applications in the diagnosis and treatment of human diseases.'

Introduzione (Teaser)

A European study worked on elucidating how phagocytes recognise apoptotic cells. Given the importance of this process in biology, the study findings have significant medical implications.

Descrizione progetto (Article)

Proper development and tissue homeostasis is highly dependent on the elimination of unwanted or aberrant cells. This is achieved through apoptosis and subsequent phagocytosis of dead cells. Failure to do so could lead to inflammation and autoimmunity.

The EU-funded 'Molecular and cellular mechanisms in phagocytosis of apoptotic cells' (AC REMOVAL MECHANISM) project investigated the molecular and cellular mechanisms associated with phagocytic recognition of apoptotic cells. The work concentrated on the previously identified Six Microns Under (SIMU) receptor. Through SIMU, macrophages and glia in the nervous system recognise and engulf apoptotic cells.

To understand how SIMU functions, researchers looked for its associating partner molecules. In this context, they characterised which SIMU domains were responsible for binding to apoptotic cells and the phagocytic surface. They identified phospholipid phosphatidylserine as a SIMU ligand on the surface of apoptotic cells. Findings revealed that additional caspase ligands were required for efficient clearance of apoptotic cells.

These findings were corroborated through experiments in Drosophila embryos clearly illustrating that additional mechanisms to SIMU signalling are in place for phagocytosis of unwanted cells. Scientists investigated the role of additional receptors (LDL and CD36) by generating flies lacking these molecules. This helped in understanding the process of apoptotic cell clearance during Drosophila embryogenesis.

Collectively, the AC REMOVAL MECHANISM study provided the basis for identifying novel actors implicated in the process of phagocytic clearance of apoptotic cells. Apart from fundamental insight into the key biological process of phagocytosis, the project findings have potential applications in the diagnosis and treatment of human diseases.