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CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity

Nature Neurosciencevolume 4pages702710 (2001) | Download Citation



Astrocytes actively participate in synaptic integration by releasing transmitter (glutamate) via a calcium-regulated, exocytosis-like process. Here we show that this process follows activation of the receptor CXCR4 by the chemokine stromal cell-derived factor 1 (SDF-1). An extraordinary feature of the ensuing signaling cascade is the rapid extracellular release of tumor necrosis factor-α (TNFα). Autocrine/paracrine TNFα-dependent signaling leading to prostaglandin (PG) formation not only controls glutamate release and astrocyte communication, but also causes their derangement when activated microglia cooperate to dramatically enhance release of the cytokine in response to CXCR4 stimulation. We demonstrate that altered glial communication has direct neuropathological consequences and that agents interfering with CXCR4-dependent astrocyte–microglia signaling prevent neuronal apoptosis induced by the HIV-1 coat glycoprotein, gp120IIIB. Our results identify a new pathway for glia–glia and glia–neuron communication that is relevant to both normal brain function and neurodegenerative diseases.

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This work was supported by grants from European Community (QLK6-CT1999-02203), Ministero Università e Ricerca Scientifica e Tecnologica of Italy (Cofin 1998-1999 and 2000-2001), Telethon-Italy (754) to A.V., Istituto Superiore di Sanita of Italy (II National Program on AIDS Research, 2/264; National Program on Alzheimer's Disease) to J.M. and European Fund for regional development (Calabria Region, POP 1994/99) to G.B. M.D. is the recipient of a post-doctoral fellowship from the Gobierno Vasco. We thank R. Paoletti, G. Racagni and S. Nicosia for support and advice; A. Pandiella, S. Vesce and P. Panzarasa for their contributions during the early phases of the project; C. Del Duca, S. Piccirilli, A. Pietropoli, E. Pilati, P. Podini, G. Racchetti, M. Treccozzi and C. Valori for their help with experiments; ALEMBIC, San Raffaele Scientific Institute, Milan, for confocal microscopy images; C. Montecucco for supplying purified tetanus neurotoxin; British Biotech Pharmaceuticals for their gift of BB3103; and D. Dunlap for the revision of the text. M. Baggiolini, D. Littman, P. Lusso, G. Poli and A. Malgaroli for commentson previous versions of the manuscript.

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Author notes

  1. Paola Bezzi and Maria Domercq: The first two authors contributed equally to this work


  1. Department of Pharmacological Sciences, Center for Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti, 9, Milan, 20133, Italy

    • Paola Bezzi
    • , Maria Domercq
    • , Liliana Brambilla
    •  & Andrea Volterra
  2. Department of Neurosciences, DIBIT, San Raffaele Institute and Vita-Salute University, Milan, 20132, Italy

    • Rossella Galli
    • , Angelo Vescovi
    •  & Jacopo Meldolesi
  3. Stem Cell Research Institute (SCRI), San Raffaele Hospital, Milan, 20132, Italy

    • Rossella Galli
    •  & Angelo Vescovi
  4. Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, Leuven, B-3000, Belgium

    • Dominique Schols
    •  & Erik De Clercq
  5. Department of Pharmaco-Biology, Calabria University at Cosenza, 87036, Italy

    • Giacinto Bagetta
  6. Institute of Immunology, Biomedical Sciences Research Center 'Al. Fleming,', Vari, 166 72, Greece

    • George Kollias


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Correspondence to Andrea Volterra.

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