Astrocytic GAP43 Induced by the TLR4/NF-[kappa]B/STAT3 Axis Attenuates Astrogliosis-Mediated Microglial Activation and Neurotoxicity

• Published in: The Journal of neuroscience 2016-02, Vol.36 (6), p.2027-2043
• Main Authors: 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
• Format: Article
• Language: English
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3457-15.2016

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-[kappa]B (NF-[kappa]B)- and interleukin-6/signal transducer and activator of transcription 3 (STAT3)-dependent transcriptional activation. The overexpression of the PKC phosphorylation-mimicking GAP43 super(S41D)(constitutive active GAP43) in astrocytes mimicked LPS-induced process arborization and elongation, while application of a NF-[kappa]B inhibitory peptide TAT-NBD or GAP43 super(S41A)(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.