HIV-1-infected and/or immune-activated macrophage-secreted TNF-α affects human fetal cortical neural progenitor cell proliferation and differentiation

Hui Peng, Nicholas Whitney, Yumei Wu, Changhai Tian, Huanyu Dou, You Zhou, Jialin Zheng

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Neurogenesis, tied to the proliferation, migration and differentiation of neural progenitor cells (NPC) is affected during neurodegenerative diseases, but how neurogenesis is affected during HIV-1 associated dementia (HAD) has not been fully addressed. Here we test the hypothesis that HIV-1-infected and/or immune-activated brain macrophages affect NPC proliferation and differentiation through the regulation of cytokines. We showed that human monocyte-derived macrophages (MDM) conditioned medium (MCM) induces a dose dependant increase in NPC proliferation. Conditioned media from lipopolysaccharide (LPS)-activated MDM (LPS-MCM) or HIV-infected MCM (HIV-MCM) induced a profound increase in NPC proliferation. HIV-infected and LPS-activated MCM (HIV+LPS_MCM) induced the most robust increase in NPC proliferation. Moreover, LPS-MCM and HIV+LPS-MCM decreased β-III-tubulin and increased GFAP expression, demonstrating an induction of gliogenesis and inhibition of neurogenesis. The increase of NPC proliferation and gliogenesis correlated with increases in production of TNF-α- by infected/ activated MDM. Although both IL-1β and TNF-α induced NPC proliferation and gliogenesis, these effects were only partially abrogated by soluble TNF-α receptors R1 and R2 (TNF-RlR2), but not by the IL-1 receptor antagonist (IL-1ra). This indicated that the HIV-1-infected/ LPS-activated MCM-mediated effects were, in part, through TNF-α. These observations were confirmed in severe combined immunodeficient (SCID) mice with HIV-1 encephalitis (HIVE). In these HIVE mice, NPC injected with HIV-infected MDM showed more astrocyte differentiation and less neuronal differentiation compared to NPC injection alone. These observations demonstrated that HIV-1-infected and immune-activated MDM could affect neurogenesis through induction of NPC proliferation, inhibition of neurogenesis, and activation of gliogenesis.

Original languageEnglish (US)
Pages (from-to)903-916
Number of pages14
JournalGlia
Volume56
Issue number8
DOIs
StatePublished - Jun 2008

Keywords

  • Differentiation
  • HIV-1
  • Macrophage
  • Neural progenitor cell
  • Proliferation
  • TNF-α

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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