Mechanisms regulating apoptotic cell clearance in health and disease

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Abstract It is truly remarkable that our bodies turn over/recycle about one million cells every second of life (0.1%- 0.4% of body mass daily). The cells that are turned over can include excess cells generated as part of normal development, homeostasis, used/aged cells, and damaged cells that arise from disease or infections. Although there are many forms of cell death, a large majority of these cells die via apoptosis. Professional phagocytes (such as macrophages and immature dendritic cells), or neighboring cells (fibroblasts and epithelial cells), as well as specialized phagocytes (such as Sertoli cells) mediate the removal of the dying cells. The prompt and efficient removal of cells is important at several levels, including `making space' for replacement by living cells, preventing inflammation, maintaining the function of the tissue/organ, and in turn, a healthy organism3. When apoptotic cells fail to be cleared promptly, this can lead to secondary necrosis and the release of their intracellular contents from uncleared cells, and a predilection to autoimmunity, atherosclerosis, and certain neurological pathologies. Moreover, how apoptotic cells that are often seen in actively growing tumors and after chemo-, radiation-, or immuno-therapies has relevance to immunosuppression or immune responses to the tumor derived cells. While the field of apoptotic cell clearance is exciting ,and studies to date have identified some of the basic steps, there are still large and significant gaps in our knowledge. Some of these include: why do we have so many engulfment receptors on phagocytes, are there unique signals via these receptors, can we possibly dial up the capacity for engulfment to dampen inflammation in specific disease conditions, and how does a phagocyte (such as a macrophage) take up so much excess `cargo' and still maintain its normal metabolomics, etc. While these are large questions unto itself, these are also inter-related, and over the past 15 years, our laboratory has obtained and used different tools to address these questions, and we have also significantly contributed to moving this field in several exciting directions. The overall goal of this MIRA project is to take novel approaches that will help us better define the key steps/molecular features of the apoptotic cell clearance process and also attempt to modulate the engulfment machinery for possible therapeutic benefits in disease models.