Metabolites released from apoptotic cells act as novel tissue messengers

Caspase-dependent apoptosis accounts for ~90% of homeostatic cell turnover in the body(1), and regulates inflammation, cell proliferation, and tissue regeneration(2–4). How apoptotic cells mediate such diverse effects is not fully understood. Here, we profiled the apoptotic ‘metabolite secretome’ and addressed their effects on the tissue neighborhood. Apoptotic lymphocytes and macrophages release specific metabolites, while retaining their membrane integrity. A subset of these metabolites is also shared across different primary cells and cell lines after apoptosis induction by different stimuli. Mechanistically, apoptotic metabolite secretome was not due to passive emptying of contents, rather orchestrated. First, caspase-mediated opening of the plasma membrane Pannexin 1 channels facilitated release of a select subset of the metabolite secretome. Second, certain metabolic pathways continue to remain active during apoptosis, with release of select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighboring cells, including suppression of inflammation, cell proliferation, and wound healing. Further, a cocktail of select apoptotic metabolites reduced disease severity in mouse models of inflammatory arthritis and lung graft rejection. These data advance the concept that apoptotic cells are not ‘inert corpses’ waiting for removal, rather release metabolites as ‘good-bye’ signals that actively modulate tissue outcomes.