Metabolites released from apoptotic cells act as tissue messengers

Christopher B. Medina, Parul Mehrotra, Sanja Arandjelovic, Justin S. A. Perry, Yizhan Guo, Sho Morioka, Brady Barron, Scott F. Walk, Bart Ghesquière, Alexander S. Krupnick, Ulrike Lorenz and Kodi S. Ravichandran ()
Additional contact information
Christopher B. Medina: University of Virginia
Parul Mehrotra: Ghent University
Sanja Arandjelovic: University of Virginia
Justin S. A. Perry: University of Virginia
Yizhan Guo: University of Virginia
Sho Morioka: University of Virginia
Brady Barron: University of Virginia
Scott F. Walk: University of Virginia
Bart Ghesquière: KU Leuven
Alexander S. Krupnick: University of Virginia
Ulrike Lorenz: University of Virginia
Kodi S. Ravichandran: University of Virginia

Nature, 2020, vol. 580, issue 7801, 130-135

Abstract: Abstract Caspase-dependent apoptosis accounts for approximately 90% of homeostatic cell turnover in the body1, and regulates inflammation, cell proliferation, and tissue regeneration2–4. How apoptotic cells mediate such diverse effects is not fully understood. Here we profiled the apoptotic metabolite secretome and determined its effects on the tissue neighbourhood. We show that 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 the induction of apoptosis by different stimuli. Mechanistically, the apoptotic metabolite secretome is not simply due to passive emptying of cellular contents and instead is a regulated process. Caspase-mediated opening of pannexin 1 channels at the plasma membrane facilitated the release of a select subset of metabolites. In addition, certain metabolic pathways continued to remain active during apoptosis, with the release of only select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighbouring cells, including suppression of inflammation, cell proliferation, and wound healing. Furthermore, a cocktail of 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 cells waiting for removal, but instead release metabolites as ‘good-bye’ signals to actively modulate outcomes in tissues.

Date: 2020
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DOI: 10.1038/s41586-020-2121-3

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