Acid sphingomyelinase activity triggers microparticle release from glial cells

Fabio Bianco, Cristiana Perrotta, Luisa Novellino, Maura Francolini, Loredana Riganti, Elisabetta Menna, Laura Saglietti, Edward H. Schuchman, Roberto Furlan, Emilio Clementi, Michela Matteoli, Claudia Verderio

Research output: Contribution to journalArticlepeer-review

Abstract

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 P2X"7, 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.

Original languageEnglish
Pages (from-to)1043-1054
Number of pages12
JournalEMBO Journal
Volume28
Issue number8
DOIs
Publication statusPublished - Apr 22 2009

Keywords

  • A-SMase
  • glia
  • IL-1b
  • microparticles
  • P2X7

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Acid sphingomyelinase activity triggers microparticle release from glial cells'. Together they form a unique fingerprint.

Cite this