Bournazou

Fadok

Hochreiter-Hufford

Huynh

Kerr

Köröskényi

Rock

Sitkovsky

Voll

Yamaguchi

eLife

English

Cells dying by apoptosis can trigger an anti-inflammatory gene response in other cells by releasing a compound called adenosine monophosphate.</jats:p

David Wallach

Andrew Kovalenko

Crossref

elifesciences.orgWallach and Kovalenko. eLife 2014;3:e02583. DOI: 10.7554/eLife.02583 1 of 3The cells in our bodies are genetically pro-grammed to undergo a natural process of self-destruction called apoptosis, after which the dying cell is removed by cells that have the ability to engulf them (‘phagocytes’). The membrane of the dying cell is still intact as it is engulfed by the phagocyte, so its contents do not come into contact with other nearby cells. Apoptosis does not trigger inflammation, whereas another form of cell death called necrosis—in which the cell membrane is ruptured—is often associated with inflammation (Kerr et al., 1972).Necrosis causes inflammation because some components of the dying cell that are capable of triggering inflammation come into contact with healthy cells nearby (Rock and Kono, 2008). At first it was assumed that the only reason why apoptosis did not cause inflammation was that all the contents of the dying cell remained inside the membrane and the phagocyte. However, it was later discovered that apoptosis can actually block inflammation (Voll et al., 1997; Fadok et al., 1998). Initial observations suggested that this anti-inflammatory effect is triggered when the phagocytes are exposed to phosphatidylserine—a molecule on the surface of apoptotic cells that has a central role in phagocytosis (Huynh et al., 2002). It seemed, therefore, that these anti-inflammatory changes could be induced only in cells intimately associated with the dying cell (Figure 1A).Now, in eLife, Shigekazu Nagata and co-workers at Kyoto University and the Osaka Bioscience Institute—including Hiroshi Yamaguchi as first author—report that apoptotic cells release a molecule called adenosine that can activate an anti-inflammatory gene response in phagocytes (Yamaguchi et al., 2014). They have also shown that adenosine activates this response by stimu-lating the A2a adenosine receptor in phagocytes.Similar results have been reported before (Sitkovsky and Ohta, 2005; Köröskényi et al., 2011), but it had been thought that the adeno-sine was generated by the phagocytes as a con-sequence of their uptake of the apoptotic cells (Figure 1B). Yamaguchi et al. now show that the adenosine comes from the apoptotic cells them-selves, with the phagocytes having only a sec-ondary role in its production. The first step involves enzymes called caspases—which have a central role in apoptosis—cleaving a membrane channel protein called pannexin-1 in the dying cells, and thereby activating it. This results in the release of adenosine monophosphate (AMP) from the dying cells. A 5′-nucleotidase expressed by the phago-cytes then removes a phosphate group from the AMP to yield adenosine. The adenosine then binds to the A2a receptor on the phagocytes to trigger an anti-inflammatory gene response (Figure 1C).Adenosine is not the only soluble molecule released by apoptotic cells to perform a specific  Copyright Wallach and Kovalenko. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.INSIGHTAPOPTOSISKeeping inflammation at bayCells dying by apoptosis can trigger an anti-inflammatory gene response in other cells by releasing a compound called adenosine monophosphate.DAVID WALLACH AND ANDREW KOVALENKORelated research article Yamaguchi H, Maruyama T, Urade Y, Nagata S. 2014. Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells. eLife 3:e02172. doi: 10.7554/eLife.02172Image AMP molecules released by apoptotic cells can trigger an anti-inflammatory response in phagocytes.Apoptosis | Keeping inflammation at bayWallach and Kovalenko. eLife 2014;3:e02583. DOI: 10.7554/eLife.02583 2 of 3Insightrole. For example, various other molecules— including lysophosphatidylcholine and the nucleo-tides ATP and UTP—act as ‘find me’ signals that attract phagocytes towards apoptotic cells (Hochreiter-Hufford and Ravichandran, 2013). Another example is an iron-binding glycoprotein called lactoferrin that inhibits the translocation of certain white blood cells, thereby apparently contributing to the anti-inflammatory effect of apoptosis (Bournazou et al., 2009).To what extent do the soluble molecules released by apoptotic cells have an effect on cells remote from the site of death? And how does the contribution of these molecules to the anti- inflammatory consequences of apoptosis com-pare with the contribution that results from direct contact between the dying cell and the cell engulfing it? Nagata and co-workers report that in a mouse model of inflammation (zymosan-induced peritonitis), deletion of either the Pannexin-1 gene or the A2a gene prolongs the inflammation. These findings support the notion that (in this experimental model) adenosine derived from apoptotic cells contributes significantly to the restriction of inflammation. More precise cell-type-specific targeting of these molecules (and other molecules that have anti-inflammatory effects) should lead to an improved understanding of their relative contributions to immune regula-tion in specific pathological situations.David Wallach is an eLife reviewing editor, and is in the Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel  d.wallach@weizmann.ac.ilAndrew Kovalenko is in the Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, IsraelCompeting interests: The authors declare that no competing interests exist.Published 25 March 2014ReferencesBournazou I, Pound JD, Duffin R, Bournazos S, Melville LA, Brown SB, Rossi AG, Gregory CD. 2009. Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin. Journal of Clinical Investigation 119:20–32. doi: 10.1172/JCI36226.Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM. 1998. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. Journal of Clinical Investigation 101:890–898. doi: 10.1172/JCI1112.Hochreiter-Hufford A, Ravichandran KS. 2013. Clearing the dead: apoptotic cell sensing, recognition, engulfment, and digestion. Cold Spring Harbor Perspectives in Biology 5:a008748. doi: 10.1101/cshperspect.a008748.Huynh ML, Fadok VA, Henson PM. 2002. Phosphatidylserine-dependent ingestion of apoptotic cells promotes TGF-beta1 secretion and the resolution Figure 1. How do apoptotic cells trigger an anti-inflammatory response in phagocytes? (A) Phosphatidylserine molecules on the surface of an apoptotic cell can bind to phosphatidylserine receptors on the surface of a phagocyte and previously it was suggested that this triggered an anti-inflammatory gene response. (B) It was also suggested that the direct apoptotic cell–phagocyte interaction shown in A also results in the release of adenosine by the phagocyte: this adenosine can bind to A2a receptors on the surface of the phagocyte and trigger an anti-inflammatory gene response. (C) Yamaguchi et al. found that the apoptotic cell releases a molecule called adenosine monophos-phate (AMP) that is converted to adenosine by a 5′-nucleotidase on the surface of the phagocyte. The adenosine can then trigger an anti-inflammatory gene response by binding to A2a receptors. Enzymes called caspases play a central role in apoptosis in a variety of ways. The action of these caspases is required for the exposure of phosphatidylserine on the surface of the apoptotic cells (A and B); they also activate a channel protein called pannexin-1 to allow the release of AMP (C).Apoptosis | Keeping inflammation at bayWallach and Kovalenko. eLife 2014;3:e02583. DOI: 10.7554/eLife.02583 3 of 3Insightof inflammation. Journal of Clinical Investigation 109:41–50. doi: 10.1172/JCI11638.Kerr JF, Wyllie AH, Currie AR. 1972. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. British Journal of Cancer 26:239–257. doi: 10.1038/bjc.1972.33.Köröskényi K, Duro E, Pallai A, Sarang Z, Kloor D, Ucker DS, Beceiro S, Castrillo A, Chawla A, Ledent CA, et al. 2011. Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation. Journal of Immunology 186:7144–7155. doi: 10.4049/jimmunol.1002284.Rock KL, Kono H. 2008. The inflammatory response to cell death. Annual Reviews of Pathology 3:99–126. doi: 10.1146/annurev.pathmechdis.3.121806.151456.Sitkovsky MV, Ohta A. 2005. The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors? Trends in Immunology 26:299–304. doi: 10.1016/j.it.2005.04.004.Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I. 1997. Immunosuppressive effects of apoptotic cells. Nature 390:350–351. doi: 10.1038/37022.Yamaguchi H, Maruyama T, Urade Y, Nagata S. 2014. Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells. eLife 3:e02172. doi: 10.7554/eLife.02172.

Keeping inflammation at bay

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Keeping inflammation at bay

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