CXCR4-activated astrocyte glutamate release via TNFa: Amplification by microglia triggers neurotoxicity

Paola Bezzi, Maria Domercq, Liliana Brambilla, Rossella Galli, Dominique Schols, Erik De Clercq, Angelo Vescovi, Giacinto Bagetta, George Kollias, Jacopo Meldolesi, Andrea Volterra

Research output: Contribution to journalArticlepeer-review

909 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)702-710
Number of pages9
JournalNature Neuroscience
Issue number7
StatePublished - 2001

ASJC Scopus subject areas

  • Neuroscience(all)


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