During animal development and in adulthood, cells undergoing apoptosis are rapidly internalized by other cells via phagocytosis (engulfment) and degraded inside phagocytes. The phagocytic removal of dying cells is an evolutionarily conserved process that has important physiological impact. The removal of apoptotic cells provides a safe means for eliminating unwanted and dangerous cells from the body. Furthermore, it prevents tissue injury, inflammatory responses, and auto-immune responses that could be induced by the content of dead cells. In addition, cells that die through necrosis, another type of cell death morphologically distinct from apoptosis and frequently caused by acute injury are also removed via phagocytosis. The removal of necrotic cells, which are associated with neurodegenerative disorders and stress responses, is considered critical for tissue regeneration. The study of the dying-cell removal process is also closely related to cancer research and treatment. My long-term objective is to understand the conserved molecular mechanism that controls the recognition, engulfment, and degradation of apoptotic cells, using the nematode Caenorhabditis elegans as a model organism. This proposal focuses on understanding the recognition of dying cells by engulfing cells, the first step of dying- cell removal. Dying cells expose "eat me" signal(s) on their outer surfaces to attract engulfing cells, which use cell-surface receptors to recognize the "eat me" signal(s) and initiate the engulfment process. A lot remains unknown about the mechanism that leads to the recognition of apoptotic cells by engulfing cells. Even less is known about how necrotic cells are recognized and removed from our bodies. We have previously identified C. elegans CED-1 as a phagocytic receptor for apoptotic cells. We have further found that phosphatidylserine (PS), a plasma membrane phospholipid, which is exposed on the outer surfaces of apoptotic cells, act as an "eat me" signal that attracts CED-1. This project investigates the molecular mechanisms leading to the exposure of PS by apoptotic and necrotic cells and the recognition of PS by CED-1 and a potential co-receptor of CED-1. Our work will identify common and different mechanisms that control the phagocytic recognition of necrotic and apoptotic cells, which die of different mechanisms. Furthermore, our work will shed light on novel mechanisms of cell-cell recognition and receptor activation during cell death and clearance.
This project studies how cells die of apoptosis (cells that commit suicide) or necrosis (cells die of injury) inside animal bodies are recognized by other cells, which leads to the internalization and digestion inside the engulfing cells. The recognition and clearance of dying cells protects humans from the harmful inflammatory and auto-immune responses that dying cells would induce if they are left in the body. Understanding the mechanisms controlling this process will have important therapeutic implications in fighting chronic inflammatory and auto-immune diseases, in treating neurodegenerative diseases and stroke, and in developing new strategies to target cancer cells for engulfment and digestion.
|Li, Zao; Venegas, Victor; Nagaoka, Yuji et al. (2015) Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms. PLoS Genet 11:e1005285|