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Apoptotic cells secrete metabolites to regulate immune homeostasis

2020; Wiley; Volume: 98; Issue: 5 Linguagem: Inglês

10.1111/imcb.12333

1440-1711

Amy A. Baxter, Ivan K. H. Poon,

Heme Oxygenase-1 and Carbon Monoxide

The rapid removal of apoptotic cells by phagocytes is a crucial homeostatic process that prevents dying cell accumulation and leakage of proinflammatory factors from dead cells into the extracellular environment. Over the past 20 years, the concept of apoptotic cell sensing by phagocytes via the release or exposure of "find-me," "keep-out," "eat-me" and "don't eat-me" signals from apoptotic cells has become central to our understanding of how apoptotic cells facilitate their clearance while promoting an anti-inflammatory response.1-5 In addition to this repertoire of signals, a novel form of intercellular communication by which apoptotic cells can regulate immune homeostasis has been reported. In a recent study by Medina et al.6 published in the journal Nature, certain cellular metabolites, termed "good-bye" signals, were shown to be selectively released by apoptotic cells and could modulate the gene expression of healthy neighboring cells to regulate inflammation. The findings from this study reflect a continuing departure from the dogma that apoptotic "corpses" are merely cellular waste requiring disposal. Work from the Center for Cell Clearance, at the University of Virginia, has defined the apoptotic cell "metabolite secretome" through a nonbiased metabolomics screen of apoptotic cell supernatants. Intriguingly, a selection of metabolites released by apoptotic cells was both caspase dependent and selective, that is, they appeared to be secreted despite other metabolites being retained within the dying cells. Notably, six metabolites (i.e. spermidine, adenosine triphosphate, adenosine monophosphate, guanosine monophosphate, creatine and glycerol-3-P) were found to be released by a range of cell types undergoing apoptosis. Continuing on from the authors previous work identifying caspase-activated Pannexin 1 (Panx1) as a key membrane channel facilitating the release of adenosine triphosphate to function as a "find-me" signal,7 20% of metabolites secreted by apoptotic cells (including the six aforesaid metabolites) were found to be dependent on Panx1 (Figure 1). The fact that only one-fifth of apoptotic cell-derived metabolites were shown to be released through Panx1 is of interest, as most metabolites are small (approximately 50–1500 Da8) and Panx1 has been suggested to facilitate the release of molecules that are up to 1000 Da.9 These observations suggest that additional mechanisms must exist to aid the release of the remaining 80% of metabolites from apoptotic cells, possibly via other membrane channels with activity regulated (directly or indirectly) by caspase activation (Figure 1). Caspase-activated Panx1 has been described to regulate a broad range of processes during apoptosis, including the recruitment of phagocytes toward dying cells though the release of "find-me" signals adenosine triphosphate and uridine triphosphate,7 the immune response through the release of "calm-down" signal adenosine monophosphate10 and other metabolites (as will be detailed later), the disassembly of apoptotic cells into fragments known as apoptotic bodies to aid cell clearance11, 12 and NLRP3 inflammasome assembly.13 Precisely how these Panx1-regulated processes intertwine to modulate cell clearance and immunity remains to be fully defined. The release of cytokines and small extracellular vesicles (EVs) from apoptotic cells has been shown to facilitate communication with neighboring cells, in particular in the context of modulating inflammation and immunity.14-16 To this end, Medina and colleagues identified that several gene programs including those associated with regulating inflammation, tissue repair and metabolism were upregulated in phagocytes exposed to apoptotic cell supernatants. Importantly, for several of these programs, upregulation occurred specifically when supernatants were derived from apoptotic cells with active Panx1 channels (Figure 1). Using a murine model of thymocyte apoptosis the authors found that in vivo Panx1-dependent metabolite release upregulated several genes in thymic phagocytic myeloid cells, in particular genes associated with anti-inflammatory processes. These observations raise the compelling question of how, under physiological settings, other extracellular factors derived from apoptotic cells might influence phagocytes in conjunction with secreted metabolites. Presumably, the release of metabolites by an apoptotic cell into the local extracellular environment would occur amidst a milieu of proteins and EVs that could affect gene expression and/or function of neighboring cells. Indeed, a previous study by Jansen and colleagues in atherosclerotic mice reported that EV-mediated transfer of microRNA from apoptotic to healthy endothelial cells downregulated expression of inflammatory markers in target cells.17 Likewise, EVs derived from apoptotic glioblastoma cells have been shown to mediate transfer of splicing factor RNA Binding Motif Protein 11 to neighboring cells, resulting in altered protein expression and promoting a more aggressive phenotype.18 Hence, how these different components could act in concert, as well as the kinetics of metabolite release in relation to EV and cytokine release is of significant interest. Medina and colleagues leave us with the intriguing concept that different cell types undergoing apoptosis can release unique combinations of metabolites, suggesting that changes in the metabolic secretome may exert different physiological and functional effects on neighboring cells. How this translates to regulation of inflammatory processes in the context of homeostasis, and moreover disease, remains largely unexplored. Following identification that the Panx1-dependent apoptotic cell metabolite secretome contains factors that could influence the gene expression of phagocytes, Medina and colleagues extended their studies to address in what pathological contexts this might operate. To this end, the effects of directly administering an exogenous metabolite mixture (coined as "MeMix",3 containing Panx1-dependent metabolites spermidine, guanosine monophosphate and inosine monophosphate) with an anti-inflammatory signature in two murine inflammatory models were examined. In the first, arthritic mice were treated by intraperitoneal administration with MeMix,3 and displayed significant reductions in inflammation and other arthritic phenotypes. In the second, a lung transplant rejection model, mice transplanted with minor antigen-mismatched lung allografts were intraperitoneally administered with MeMix3 post-transplant. Remarkably, MeMix3-treated mice displayed reduced organ rejection. Together, these findings provide proof-of-concept evidence that metabolites, in particular those secreted during apoptosis, can exhibit anti-inflammatory properties in disease settings. It should be noted that the application of metabolites for therapeutic purposes is an area of growing interest, with recently reported examples including the use of microbiota-derived metabolites in the maintenance of intestinal homeostasis,19 and the treatment of retinal neurodegeneration with oxidative phosphorylation and tricarboxylic acid cycle metabolites.20 Whether MeMix3 or other combinations of metabolites found in the apoptotic cell metabolite secretome could be developed as new therapeutics for inflammatory diseases would certainly be of interest in future studies. Furthermore, it is also of importance to elucidate the molecular factors on phagocytes that could meditate the detection of apoptotic cell-derived metabolites (Figure 1), such as the potential role of solute carrier transporters,21 transient receptor potential cation channel subfamily V member 1 (TRPV1) channels22 and N-methyl-D-aspartate receptors23 in sensing apoptotic cells. Saying good-bye can be hard, and dying cells have surely developed a remarkable way to part with their neighboring cells. The elegant and thought-provoking work by Medina and colleagues has opened a new area of research, with many questions remaining to be explored. The authors declare no conflicts of interest.