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

Abstract

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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Figure 1: SDF-1α induces Ca2+-dependent glutamate release from hippocampal slices with blocked neuronal exocytosis and from cultured astrocytes.
Figure 2: Involvement of TNFα in the SDF-1α-evoked glutamate release.
Figure 3: Signaling cascade coupling CXCR4 activation to glutamate release in astrocytes; the key roles of TNFα and PGE2.
Figure 4: Reactive microglia amplify CXCR4-dependent glutamate release via a synergic, TNFα-mediated interaction with the astrocytes.
Figure 5: The CXCR4-dependent glutamate release pathway is activated by the HIV-1 envelope glycoprotein gp120IIIB and is implicated in its neurotoxic action.
Figure 6: Proposed sequence of signaling events coupling in astrocytes

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Acknowledgements

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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Correspondence to Andrea Volterra.

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Bezzi, P., Domercq, M., Brambilla, L. et al. CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nat Neurosci 4, 702–710 (2001). https://doi.org/10.1038/89490

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