PMID- 21637744
OWN - NLM
STAT- MEDLINE
DCOM- 20110929
LR  - 20211109
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 6
IP  - 5
DP  - 2011
TI  - HIV-1-infected and immune-activated macrophages induce astrocytic differentiation 
      of human cortical neural progenitor cells via the STAT3 pathway.
PG  - e19439
LID - 10.1371/journal.pone.0019439 [doi]
LID - e19439
AB  - 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-alpha), 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-1beta and TNF-alpha) 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.
FAU - Peng, Hui
AU  - Peng H
AD  - Laboratory of Neuroimmunology and Regenerative Therapy, University of Nebraska 
      Medical Center, Omaha, Nebraska, United States of America. hpeng@unmc.edu
FAU - Sun, Lijun
AU  - Sun L
FAU - Jia, Beibei
AU  - Jia B
FAU - Lan, Xiqian
AU  - Lan X
FAU - Zhu, Bing
AU  - Zhu B
FAU - Wu, Yumei
AU  - Wu Y
FAU - Zheng, Jialin
AU  - Zheng J
LA  - eng
GR  - P01 NS043985/NS/NINDS NIH HHS/United States
GR  - P01NS43985/NS/NINDS NIH HHS/United States
GR  - R21 NS066841/NS/NINDS NIH HHS/United States
GR  - R01 NS061642/NS/NINDS NIH HHS/United States
GR  - R01NS61642/NS/NINDS NIH HHS/United States
GR  - R01 NS041858/NS/NINDS NIH HHS/United States
GR  - P20RR15635/RR/NCRR NIH HHS/United States
GR  - P20 RR015635/RR/NCRR NIH HHS/United States
GR  - R01 NS41858/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20110527
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Lipopolysaccharides)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.10.2 (Janus Kinases)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Astrocytes/*cytology/drug effects
MH  - *Cell Differentiation/drug effects
MH  - Cerebral Cortex/cytology
MH  - Enzyme Activation/drug effects
MH  - HIV Infections/*immunology/virology
MH  - HIV-1/drug effects/immunology
MH  - Humans
MH  - Janus Kinases/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophage Activation/drug effects/*immunology
MH  - Macrophages/drug effects/enzymology/immunology/*virology
MH  - Mice
MH  - Monocytes/cytology/drug effects/metabolism
MH  - Neural Stem Cells/*cytology/drug effects/metabolism
MH  - Neurogenesis/drug effects
MH  - RNA, Small Interfering/metabolism
MH  - STAT3 Transcription Factor/genetics/*metabolism
MH  - Signal Transduction/drug effects
MH  - Tumor Necrosis Factor-alpha/pharmacology
PMC - PMC3103496
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2011/06/04 06:00
MHDA- 2011/10/01 06:00
PMCR- 2011/05/27
CRDT- 2011/06/04 06:00
PHST- 2010/08/20 00:00 [received]
PHST- 2011/04/06 00:00 [accepted]
PHST- 2011/06/04 06:00 [entrez]
PHST- 2011/06/04 06:00 [pubmed]
PHST- 2011/10/01 06:00 [medline]
PHST- 2011/05/27 00:00 [pmc-release]
AID - PONE-D-10-00609 [pii]
AID - 10.1371/journal.pone.0019439 [doi]
PST - ppublish
SO  - PLoS One. 2011;6(5):e19439. doi: 10.1371/journal.pone.0019439. Epub 2011 May 27.