Astrocytic GAP43 induced by the TLR4/NF-κB/STAT3 axis attenuates astrogliosis-mediated microglial activation and neurotoxicity

Chia Chi Hung, Chun Hua Lin, Hsuan Chang, Chen Yu Wang, Shang Hsuan Lin, Pei Chien Hsu, Yu Yo Sun, Teng Nan Lin, Feng Shiun Shie, Lung Sen Kao, Chih Ming Chou, Yi-Hsuan Lee

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Growth-associated protein 43 (GAP43), a protein kinase C (PKC)-activated phosphoprotein, is often implicated in axonal plasticity and regeneration. In this study, we found that GAP43 can be induced by the endotoxin lipopolysaccharide (LPS) in rat brain astrocytes both in vivo and in vitro. The LPS-induced astrocytic GAP43 expression was mediated by Toll-like receptor 4 and nuclear factor-κB (NF-κB)-and interleukin-6/signal transducer and activator of transcription 3 (STAT3)-dependent transcriptional activation. The overexpression of the PKC phosphorylation-mimicking GAP43S41D (constitutive active GAP43) in astrocytes mimicked LPS-induced process arborization and elongation, while application of a NF-[1]B inhibitory peptide TAT-NBD or GAP43S41A (dominant-negative GAP43) or knockdown of GAP43 all inhibited astrogliosis responses. Moreover, GAP43 knockdown aggravated astrogliosis-induced microglial activation and expression of proinflammatory cytokines. We also show that astrogliosis-conditioned medium from GAP43 knock-down astrocytes inhibited GAP43 phosphorylation and axonal growth, and increased neuronal damage in cultured rat cortical neurons. These proneurotoxic effects of astrocytic GAP43 knockdown were accompanied by attenuated glutamate uptake and expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in LPS-treated astrocytes. The regulation of EAAT2 expression involves actin polymerization-dependent activation of the transcriptional coactivator megakaryoblastic leukemia 1 (MKL1), which targets the serum response elements in the promoter of rat Slc1a2 gene encoding EAAT2. In sum, the present study suggests that astrocytic GAP43 mediates glial plasticity during astrogliosis, and provides beneficial effects for neuronal plasticity and survival and attenuation of microglial activation.

Original languageEnglish
Pages (from-to)2027-2043
Number of pages17
JournalJournal of Neuroscience
Volume36
Issue number6
DOIs
Publication statusPublished - Feb 10 2016

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GAP-43 Protein
STAT3 Transcription Factor
Excitatory Amino Acid Transporter 2
Astrocytes
Lipopolysaccharides
Protein Kinase C
Transcriptional Activation
Serum Response Element
Phosphorylation
Amino Acid Transport System X-AG
Toll-Like Receptor 4
Neuronal Plasticity
Interleukins
Phosphoproteins
Conditioned Culture Medium
Endotoxins
Neuroglia
Polymerization
Actins
Regeneration

Keywords

  • Astrogliosis
  • EAAT2
  • GAP43
  • Microglial activation
  • MKL1
  • Neurotoxicity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Astrocytic GAP43 induced by the TLR4/NF-κB/STAT3 axis attenuates astrogliosis-mediated microglial activation and neurotoxicity. / Hung, Chia Chi; Lin, Chun Hua; Chang, Hsuan; Wang, Chen Yu; Lin, Shang Hsuan; Hsu, Pei Chien; Sun, Yu Yo; Lin, Teng Nan; Shie, Feng Shiun; Kao, Lung Sen; Chou, Chih Ming; Lee, Yi-Hsuan.

In: Journal of Neuroscience, Vol. 36, No. 6, 10.02.2016, p. 2027-2043.

Research output: Contribution to journalArticle

Hung, CC, Lin, CH, Chang, H, Wang, CY, Lin, SH, Hsu, PC, Sun, YY, Lin, TN, Shie, FS, Kao, LS, Chou, CM & Lee, Y-H 2016, 'Astrocytic GAP43 induced by the TLR4/NF-κB/STAT3 axis attenuates astrogliosis-mediated microglial activation and neurotoxicity', Journal of Neuroscience, vol. 36, no. 6, pp. 2027-2043. https://doi.org/10.1523/JNEUROSCI.3457-15.2016
Hung, Chia Chi ; Lin, Chun Hua ; Chang, Hsuan ; Wang, Chen Yu ; Lin, Shang Hsuan ; Hsu, Pei Chien ; Sun, Yu Yo ; Lin, Teng Nan ; Shie, Feng Shiun ; Kao, Lung Sen ; Chou, Chih Ming ; Lee, Yi-Hsuan. / Astrocytic GAP43 induced by the TLR4/NF-κB/STAT3 axis attenuates astrogliosis-mediated microglial activation and neurotoxicity. In: Journal of Neuroscience. 2016 ; Vol. 36, No. 6. pp. 2027-2043.
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AU - Wang, Chen Yu

AU - Lin, Shang Hsuan

AU - Hsu, Pei Chien

AU - Sun, Yu Yo

AU - Lin, Teng Nan

AU - Shie, Feng Shiun

AU - Kao, Lung Sen

AU - Chou, Chih Ming

AU - Lee, Yi-Hsuan

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