Metabolites released from apoptotic cells act as tissue messengers
Christopher B Medina1,2, Parul Mehrotra3, Sanja Arandjelovic1,2
1Center for Cell Clearance, University of Virginia, Charlottesville, VA, USA.
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.
Insights
Apoptotic cells actively release specific metabolites, not passively, to signal neighboring cells. This regulated
Area of Science:
- Cell Biology
- Immunology
- Metabolomics
Background:
- Caspase-dependent apoptosis is crucial for tissue homeostasis, regulating inflammation, proliferation, and regeneration.
- The precise mechanisms by which apoptotic cells exert diverse effects on their tissue environment remain incompletely understood.
Purpose of the Study:
- To profile the metabolite secretome of apoptotic cells.
- To investigate the functional impact of these released metabolites on neighboring cells and in disease models.
Main Methods:
- Profiling of the apoptotic metabolite secretome from various cell types.
- Investigating the role of caspase-mediated pannexin 1 channel opening in metabolite release.
- Assessing the effects of apoptotic secretome on gene expression in healthy cells.
- Evaluating the therapeutic potential of apoptotic metabolites in mouse models of inflammatory arthritis and lung-graft rejection.
Main Results:
- Apoptotic cells, while maintaining membrane integrity, release specific, regulated subsets of metabolites.
- Metabolite release is facilitated by caspase-mediated pannexin 1 channel opening, with ongoing metabolic activity.
- The apoptotic secretome suppresses inflammation, cell proliferation, and promotes wound healing in recipient cells.
- A cocktail of apoptotic metabolites significantly reduced disease severity in inflammatory arthritis and lung-graft rejection models.
Conclusions:
- Apoptotic cells actively communicate with their surroundings through a regulated release of metabolites, termed the 'apoptotic secretome'.
- This secretome acts as a 'good-bye' signal, actively modulating tissue responses to promote resolution and homeostasis.
- These findings redefine the role of apoptotic cells from passive entities to active regulators of tissue microenvironments and disease outcomes.
Related Concept Videos
01:17Phagocytosis of Apoptotic Cells
Normal cells contain receptors that prevent them from being recognized...
01:30Apoptosis
01:17The Extrinsic Apoptotic Pathway
01:31The Intrinsic Apoptotic Pathway
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...