Meals for macrophages – investigating how macrophages engulf and process dying cells in vivo

A critical role for phagocytic cells such as macrophages is the engulfment and subsequent degradation of dying cells and debris. Failure to clear targets such as apoptotic cells can lead to damaging autoimmune conditions and immune cell dysfunction (Morioka et al., 2019; Roddie et al., 2019). This project aims to understand how macrophages engulf and process dying cells in vivo and how apoptotic cell fragmentation assists in these fundamental cellular events.

We use the fruit fly (Drosophila melanogaster) to understand regulation of the innate immune system, taking advantage of this organism’s lack of genetic redundancy, excellent genetic tools and imaging capabilities and the presence of blood cells called hemocytes. Hemocytes are comprised of three types of cell, one of which is a macrophage lineage also known as plasmatocytes (Ratheesh et al., 2015). These macrophages are critical for normal development and immunity of this organism (Defaye et al., 2009), with apoptotic cell clearance a key role for these innate immune cells; apoptotic cell clearance also helps sculpt and programme the subsequent behaviour of these immune cells (Weavers et al., 2016; Coates et al., 2020).

The aims of this project are to understand how the shape changes that apoptotic cells undergo contribute and regulate their subsequent engulfment, degradation and re-programming of macrophages. We will use fly genetics to manipulate apoptotic cell death processes and cell shape changes specifically within dying cells. The University of Sheffield’s state-of-the-art live imaging facilities will be used to follow and understand these fundamental processes live, in vivo. We will translate novel findings to vertebrates and demonstrate relevance to higher organisms through the use of zebrafish and human cell culture.

This project involves fly and zebrafish genetics, cell culture, molecular biology, cell biology techniques, live cell imaging, confocal microscopy and image analysis. The project will be hosted in the world-leading Bateson Centre at the University of Sheffield, which aims to use non-mammalian model organisms to understand developmental biology and human disease processes.