Deciphering metabolite-based communication between dying cells and the tissue neighborhood

Death and turnover of cells occurs routinely in the human body as a part of normal healthy living as well as during infection recovery. Among the modes of death, apoptosis is non-inflammatory, while pyroptosis and necroptosis are processes relevant for infection resistance and are pro-inflammatory. Pyroptosis and necroptosis cause pores in the cell membrane releasing contents of the cell that contribute to inducing inflammation. By screening for metabolites released from dying cells, we have recently found that apoptotic cells secrete specific set of metabolites in a regulated manner via membrane channels. Since apoptosis has different consequences from pyroptosis and necroptosis, in this proposal we will address whether pyroptotic and necroptotic cells also release specific set of metabolites before they rupture, and how they differ from apoptotic secretions. Further, we will address how the diverse metabolic messages from the three cell death modalities affect transcriptional, immune and inflammatory outcomes in their neighboring cells. The ultimate aim of this work is to identify specific metabolites that may be used to influence inflammation, infection resistance or tissue repair.