Cannibal Cells: How Cells Clear Dangerous Debris

Project Overview Billions of cells die every day and must be efficiently removed to maintain tissue health. While the clearance of apoptotic cells is well understood, it remains unclear whether and how the immune system removes cells that die by necrosis or necroptosis, a regulated inflammatory form of cell death driven by RIPK1, RIPK3 and MLKL. During necroptosis, cells rupture and release their contents into surrounding tissues, but the fate of this debris, and how immune cells respond to it, is a major open question in cell biology. This PhD project will investigate how macrophages, the body’s professional clean-up cells, recognise, engulf and process necroptotic debris. Unlike apoptotic cells, necroptotic cells display a complex mixture of ‘eat-me’ and ‘don’t-eat-me’ signals, and macrophage responses range from partial uptake to complete engulfment. Whether macrophages activate specialised genetic programs to handle necroptotic debris, and whether those responses drive tissue repair or inflammation, are precisely the questions this project sets out to answer. A particular focus will be how these processes are influenced by time of day, biological sex and ageing. Because immune cell function is regulated by circadian rhythms and declines with age, the same cell death event may be resolved efficiently at one time of day, or in a young cell, and poorly in another. By combining advanced transcriptomics, imaging and functional assays, this project aims to generate the first time-resolved understanding of how macrophages respond to necroptotic debris and how these responses influence tissue homeostasis and repair. These questions are particularly pressing in atherosclerosis, where necroptotic cell death and failed debris clearance drive the growth of the lipid-rich plaques that cause heart attack and stroke. Research Aims The project can be tailored to the student’s interests and may include: • Defining the transcriptional programs activated in macrophages exposed to necroptotic debris. • Identifying genes that regulate debris recognition, engulfment and degradation. • Determining how circadian rhythms influence macrophage responses • Investigating how ageing alters debris clearance and inflammatory responses. • Testing whether key pathways are conserved across experimental models. Training and Techniques Students will receive multidisciplinary training in: • Transcriptomics, bioinformatics and nascent RNA sequencing • CRISPR/Cas9 gene editing and gene manipulation technologies • Flow cytometry-based engulfment and digestion assays • Confocal and live-cell imaging • Optogenetic control of cell death pathways • Primary immune cell culture and in vivo models • Cell death biology, immunology and metabolic analysis The project is supported by a multidisciplinary supervisory team with expertise in macrophage biology, transcriptional regulation, circadian biology and regulated cell death. Candidate Background Applicants with Honours, Masters or equivalent research experience in immunology, cell biology, molecular biology, genetics, biochemistry, biomedical science or related disciplines are encouraged to apply. Prior laboratory experience is advantageous but not essential. Candidates interested in developing both experimental and computational skills are particularly encouraged. Expected Outcomes This project will provide fundamental insights into how the immune system manages inflammatory cell death and will establish whether macrophages deploy specialised gene programs to clear necroptotic debris. The findings will be relevant to tissue repair, ageing, infection, inflammatory disease and cardiovascular conditions such as atherosclerosis. Students can expect opportunities for first-author publications and presentations at national and international conferences.