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  • The EMBO Journal (2009) 28, 1043 - 1054
  • doi:10.1038/emboj.2009.45

Published online: 19 March 2009



There is a Corrigendum (May 2009) associated with this Article.

Acid sphingomyelinase activity triggers microparticle release from glial cellsEMBO Open

Fabio Bianco1,2,a, Cristiana Perrotta3,a, Luisa Novellino1,a, Maura Francolini1, Loredana Riganti1, Elisabetta Menna1, Laura Saglietti1, Edward H Schuchman4, Roberto Furlan5, Emilio Clementi6,7, Michela Matteoli1,8 and Claudia Verderio1

  1. CNR Institute of Neuroscience and Department of Medical Pharmacology, University of Milano, Milano, Italy
  2. NeuroZone srl, Milano, Italy
  3. Hospital of Luigi Sacco, Milano, Italy
  4. Department of Genetics and Genomic Science, Mount Sinai School of Medicine, New York, NY, USA
  5. Clinical Neuroimmunology Unit, Institute of Experimental Neurology, S Raffaele Scientific Instute, Milano, Italy
  6. Medea Science Institute, Bosisio Parini, Italy
  7. Department of Preclinical Science, LITA-Vialba University of Milano, Milano, Italy
  8. Fondazione Don Gnocchi, Milano, Italy

Correspondence to:

Claudia Verderio, CNR Institute of Neuroscience, Department of Medical Pharmacology, Via Vanvitelli 32, 20129 Milano, Italy. Tel.: +39 02 50317097; Fax: +39 02 7490574; E-mail: c.verderio@in.cnr.it

aThese authors equally contributed to this work

Received 21 November 2008; Accepted 29 January 2009

We have earlier shown that microglia, the immune cells of the CNS, release microparticles from cell plasma membrane after ATP stimulation. These vesicles contain and release IL-1beta, a crucial cytokine in CNS inflammatory events. In this study, we show that microparticles are also released by astrocytes and we get insights into the mechanism of their shedding. We show that, on activation of the ATP receptor P2X7, microparticle shedding is associated with rapid activation of acid sphingomyelinase, which moves to plasma membrane outer leaflet. ATP-induced shedding and IL-1beta release are markedly reduced by the inhibition of acid sphingomyelinase, and completely blocked in glial cultures from acid sphingomyelinase knockout mice. We also show that p38 MAPK cascade is relevant for the whole process, as specific kinase inhibitors strongly reduce acid sphingomyelinase activation, microparticle shedding and IL-1beta release. Our results represent the first demonstration that activation of acid sphingomyelinase is necessary and sufficient for microparticle release from glial cells and define key molecular effectors of microparticle formation and IL-1beta release, thus, opening new strategies for the treatment of neuroinflammatory diseases.

  • Keywords:

    • A-SMase,
    • glia,
    • IL-1beta,
    • microparticles,
    • P2X7

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.

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