Nature Neuroscience
4, 702 - 710 (2001)
doi:10.1038/89490
CXCR4-activated astrocyte glutamate release via TNF : amplification by microglia triggers neurotoxicityPaola Bezzi1, 7, Maria Domercq1, 7, Liliana Brambilla1, Rossella Galli2, 3, Dominique Schols4, Erik De Clercq4, Angelo Vescovi2, 3, Giacinto Bagetta5, George Kollias6, Jacopo Meldolesi2
& Andrea Volterra11
Department of Pharmacological Sciences, Center for Excellence on Neurodegenerative Diseases, University of Milan, Via Balzaretti, 9, 20133 Milan, Italy
2
DIBIT, Department of Neurosciences, San Raffaele Institute and Vita-Salute University, 20132 Milan, Italy
3
Stem Cell Research Institute (SCRI), San Raffaele Hospital, 20132 Milan, Italy
4
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
5
Department of Pharmaco-Biology, Calabria University at Cosenza, 87036, Italy
6
Institute of Immunology, Biomedical Sciences Research Center 'Al. Fleming,', 166 72 Vari, Greece
7
The first two authors contributed equally to this work
Correspondence should be addressed to Andrea Volterra andrea.volterra@unimi.itAstrocytes 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- (TNF). Autocrine/paracrine TNF-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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