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Interferon-alpha reduces human hippocampal neurogenesis and increases apoptosis via activation of distinct STAT1-dependent mechanisms

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Alessandra Borsini, Annamaria Cattaneo, Chiara Malpighi, Sandrine Thuret, Neil A Harrison, Edward Bullmore, Petra E. Vértes, Rudolf Cardinal, Sylvia Richardson, Gwenael Leday, Tom Freeman, David Hume, Tim Regan, Zhaozong Wu, Robert Stewart, David Chandran, Livia Carvalho, Joshua Bell, Luis Henrique Souza-Teodoro, Hugh Perry & 9 more Wayne Drevets, Gayle M Wittenberg, Yu Sun, Declan Jones, Shahid Khan, Annie Stylianou, Robert B Henderson, Patricia Ana Zunszain, Carmine Maria Pariante

Original languageEnglish
JournalInternational Journal of Neuropsychopharmacology
Early online date10 Oct 2017
DOIs
Publication statusE-pub ahead of print - 10 Oct 2017

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Abstract

Background: In humans, interferon-α treatment for chronic viral hepatitis is a well-recognized clinical model for inflammationinduced depression, but the molecular mechanisms underlying these effects are not clear. Following peripheral administration in rodents, interferon-α induces signal transducer and activator of transcription-1 (STAT1) within the hippocampus and disrupts hippocampal neurogenesis. Methods: We used the human hippocampal progenitor cell line HPC0A07/03C to evaluate the effects of 2 concentrations of interferon-α, similar to those observed in human serum during its therapeutic use (500 pg/mL and 5000 pg/mL), on neurogenesis and apoptosis. Results: Both concentrations of interferon-α decreased hippocampal neurogenesis, with the high concentration also increasing apoptosis. Moreover, interferon-α increased the expression of interferon-stimulated gene 15 (ISG15), ubiquitin-specific peptidase 18 (USP18), and interleukin-6 (IL-6) via activation of STAT1. Like interferon-α, co-treatment with a combination of ISG15, USP18, and IL-6 was able to reduce neurogenesis and enhance apoptosis via further downstream activation of STAT1. Further experiments showed that ISG15 and USP18 mediated the interferon-α-induced reduction in neurogenesis (potentially through upregulation of the ISGylation-related proteins UBA7, UBE2L6, and HERC5), while IL-6 mediated the interferonα-induced increase in apoptosis (potentially through downregulation of aquaporin 4). Using transcriptomic analyses, we showed that interferon-α regulated pathways involved in oxidative stress and immune response (e.g., Nuclear Factor (erythroid-derived 2)-like 2 [Nrf2] and interferon regulatory factor [IRF] signaling pathway), neuronal formation (e.g., CAMP response element-binding protein [CREB] signaling), and cell death regulation (e.g., tumor protein(p)53 signaling). Conclusions: We identify novel molecular mechanisms mediating the effects of interferon-α on the human hippocampus potentially involved in inflammation-induced neuropsychiatric symptoms.

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