Acid sphingomyelinase activity triggers microparticle release from glial cells

• Fabio Bianco ^[1] ; Cristiana Perrotta ^[2] ; Luisa Novellino ^[3] ; Maura Francolini ^[3] ; Loredana Riganti ^[3] ; Elisabetta Menna ^[3] ; Laura Saglietti ^[3] ; Edward H Schuchman ^[4] ; Roberto Furlan ^[5] ; Emilio Clementi ^[6] ; Michela Matteoli ^[7] ; Claudia Verderio ^[3]
  1. [1] CNR Institute of Neuroscience and Department of Medical Pharmacology, University of Milano, Milano, Italy; NeuroZone srl, Milano, Italy
  2. [2] Hospital of Luigi Sacco, Milano, Italy
  3. [3] CNR Institute of Neuroscience and Department of Medical Pharmacology, University of Milano, Milano, Italy
  4. [4] Department of Genetics and Genomic Science, Mount Sinai School of Medicine, New York, NY, USA
  5. [5] Clinical Neuroimmunology Unit, Institute of Experimental Neurology, S Raffaele Scientific Instute, Milano, Italy
  6. [6] Medea Science Institute, Bosisio Parini, Italy; Department of Preclinical Science, LITA-Vialba University of Milano, Milano, Italy
  7. [7] CNR Institute of Neuroscience and Department of Medical Pharmacology, University of Milano, Milano, Italy; Fondazione Don Gnocchi, Milano, Italy

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• Localización: EMBO journal: European Molecular Biology Organization, ISSN 0261-4189, Vol. 28, Nº. 8, 2009, págs. 1043-1054
• Idioma: inglés
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  • 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-1β, 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-1β 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-1β 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-1β release, thus, opening new strategies for the treatment of neuroinflammatory diseases.