HIV-1-infected and immune-activated macrophages induce astrocytic differentiation of human cortical neural progenitor cells via the STAT3 pathway

Hui Peng, Lijun Sun, Beibei Jia, Xiqian Lan, Bing Zhu, Yumei Wu, Jialin C Zheng

Research output: Contribution to journalArticle

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Abstract

Diminished adult neurogenesis is considered a potential mechanism in the pathogenesis of HIV-1-associated dementia (HAD). In HAD, HIV-1-infected and immune-activated brain mononuclear phagocytes (MP; perivascular macrophages and microglia) drive central nervous system (CNS) inflammation and may alter normal neurogenesis. We previously demonstrated HIV-1-infected and lipopolysaccharide (LPS) activated monocyte-derived macrophages (MDM) inhibit human neural progenitor cell (NPC) neurogenesis, while enhancing astrogliogenesis through the secretion of the inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), in vitro and in vivo. Here we further test the hypothesis that HIV-1-infected/activated MDM promote NPC astrogliogenesis via activation of the transcription factor signal transducer and activator of transcription 3 (STAT3), a critical factor for astrogliogenesis. Our results show that LPS-activated MDM-conditioned medium (LPS-MCM) and HIV-infected/LPS-activated MDM-conditioned medium (LPS+HIV-MCM) induced Janus kinase 1 (Jak1) and STAT3 activation. Induction of the Jak-STAT3 activation correlated with increased glia fibrillary acidic protein (GFAP) expression, demonstrating an induction of astrogliogenesis. Moreover, STAT3-targeting siRNA (siSTAT3) decreased MCM-induced STAT3 activation and NPC astrogliogenesis. Furthermore, inflammatory cytokines (including IL-6, IL-1β and TNF-α) produced by LPS-activated and/or HIV-1-infected MDM may contribute to MCM-induced STAT3 activation and astrocytic differentiation. These observations were confirmed in severe combined immunodeficient (SCID) mice with HIV-1 encephalitis (HIVE). In HIVE mice, siRNA control (without target sequence, sicon) pre-transfected NPCs injected with HIV-1-infected MDM showed more astrocytic differentiation and less neuronal differentiation of NPCs as compared to NPC injection alone. siSTAT3 abrogated HIV-1-infected MDM-induced astrogliogenesis of injected NPCs. Collectively, these observations demonstrate that HIV-1-infected/activated MDM induces NPC astrogliogenesis through the STAT3 pathway. This study generates important data elucidating the role of brain inflammation in neurogenesis and may provide insight into new therapeutic strategies for HAD.

Original languageEnglish (US)
Article numbere19439
JournalPloS one
Volume6
Issue number5
DOIs
StatePublished - Jun 1 2011

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STAT3 Transcription Factor
Macrophages
Human immunodeficiency virus 1
stem cells
HIV-1
macrophages
Stem Cells
transcription (genetics)
monocytes
Lipopolysaccharides
Chemical activation
neurogenesis
lipopolysaccharides
Neurogenesis
Multicarrier modulation
Transcriptional Activation
dementia
Encephalitis
encephalitis
Conditioned Culture Medium

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

HIV-1-infected and immune-activated macrophages induce astrocytic differentiation of human cortical neural progenitor cells via the STAT3 pathway. / Peng, Hui; Sun, Lijun; Jia, Beibei; Lan, Xiqian; Zhu, Bing; Wu, Yumei; Zheng, Jialin C.

In: PloS one, Vol. 6, No. 5, e19439, 01.06.2011.

Research output: Contribution to journalArticle

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AU - Sun, Lijun

AU - Jia, Beibei

AU - Lan, Xiqian

AU - Zhu, Bing

AU - Wu, Yumei

AU - Zheng, Jialin C

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