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- Title
Astrocytes mediate HIV-1 Tat-induced neuronal damage via ligand-gated ion channel P2X7R.
- Authors
Tewari, Manju; Monika, ; Varghese, Rebu K; Menon, Malini; Seth, Pankaj
- Abstract
During human immunodeficiency virus (HIV)-1 infection, perturbations in neuron-glia interactions may culminate in neuronal damage. Recently, purinergic receptors have been implicated in the promotion of virus-induced neurotoxicity and supporting the viral life cycle at multiple stages. The astrocytes robustly express purinergic receptors. We therefore sought to examine if P2X7R, a P2X receptor subtype, can mediate HIV-1 Tat-induced neuronal apoptosis. Tat augmented the expression of P2X7R in astrocytes. Our data reveal the involvement of P2X7R in Tat-mediated release of monocyte chemoattractant protein (MCP-1) /chemokine (C-C motif) ligand 2 (CCL2) from the astrocytes. P2X7R antagonists, such as the oxidized ATP, A438079, brilliant blue G, and broad spectrum P2 receptor antagonist suramin, attenuated Tat-induced CCL2 release in a calcium- and extracellular signal-regulated kinase (ERK)1/2-dependent manner. Calcium chelators, (1,2-bis(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid) acetoxymethyl ester and EGTA, and ERK1/2 inhibitor U0126 abolished chemokine (C-C motif) ligand 2 release from astrocytes. Furthermore, in human neuronal cultures, we demonstrated P2X7R involvement in Tat-mediated neuronal death. Importantly, in the TUNEL assay, the application of P2X7R-specific antagonists or the knockdown of P2X7R in human astrocytes reduced HIV-Tat-induced neuronal death significantly, underlining the critical role of P2X7R in Tat-mediated neurotoxicity. Our study provides novel insights into astrocyte-mediated neuropathogenesis in HIV-1 infection and a novel target for therapeutic management of neuroAIDS.
- Subjects
HIV infections; ASTROCYTES; LIGAND-gated ion channels; PURINERGIC receptors; NEUROTOXICOLOGY; MONOCYTE chemotactic factor
- Publication
Journal of Neurochemistry, 2015, Vol 132, Issue 4, p464
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.12953