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* Medical Research Council, Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom;
Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642; and
Centre d’Immunologie de Marseille-Luminy, Parc Scientifique et Technologique de Luminy, Marseille, France
Patterns of change in cell volume and plasma membrane phospholipid distribution during cell death are regarded as diagnostic means of distinguishing apoptosis from necrosis, the former being associated with cell shrinkage and early phosphatidylserine (PS) exposure, whereas necrosis is associated with cell swelling and consequent lysis. We demonstrate that cell volume regulation during lymphocyte death stimulated via the purinergic receptor P2X7 is distinct from both. Within seconds of stimulation, murine lymphocytes undergo rapid shrinkage concomitant with, but also required for, PS exposure. However, within 2 min shrinkage is reversed and swelling ensues ending in cell rupture. P2X7-induced shrinkage and PS translocation depend upon K+ efflux via KCa3.1, but use a pathway of Cl– efflux distinct from that previously implicated in apoptosis. Thus, P2X7 stimulation activates a novel pathway of cell death that does not conform to those conventionally associated with apoptosis and necrosis. The mixed apoptotic/necrotic phenotype of P2X7-stimulated cells is consistent with a potential role for this death pathway in lupus disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants R01 DE009692 (to J.E.M. and M.G.-B.) and R37 DE008921 (to J.E.M. and S.D.) from the National Institutes of Health. S.T., J.I.E., and C.F.H. were also supported by the Medical Research Council of the United Kingdom. G.C. was supported by funding from the Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, and the European Union.
2 Address correspondence and reprint requests to Dr. James I. Elliott, Medical Research Council, Clinical Sciences Centre, Faculty of Medicine, Imperial College Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail address: james.elliott{at}imperial.ac.uk
3 Abbreviations used in this paper: PS, phosphatidylserine; HMGB1, high mobility group box 1; PI, propidium iodide; MC540, merocyanine 540; AVD, apoptotic volume decrease; FSC, forward light scatter; VRAC, volume-regulated anion channel.
4 The online version of this article contains supplemental material.
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  S. R. J. Taylor, M. Gonzalez-Begne, D. K. Sojka, J. C. Richardson, S. A. Sheardown, S. M. Harrison, C. D. Pusey, F. W. K. Tam, and J. I. Elliott Lymphocytes from P2X7-deficient mice exhibit enhanced P2X7 responses J. Leukoc. Biol., June 1, 2009; 85(6): 978 - 986. [Abstract] [Full Text] [PDF]
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 S. R.J. Taylor, C. M. Turner, J. I. Elliott, J. McDaid, R. Hewitt, J. Smith, M. C. Pickering, D. L. Whitehouse, H. T. Cook, G. Burnstock, et al. P2X7 Deficiency Attenuates Renal Injury in Experimental Glomerulonephritis J. Am. Soc. Nephrol., June 1, 2009; 20(6): 1275 - 1281. [Abstract] [Full Text] [PDF]
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