PMID- 26865625 OWN - NLM STAT- MEDLINE DCOM- 20160701 LR - 20220309 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 36 IP - 6 DP - 2016 Feb 10 TI - Astrocytic GAP43 Induced by the TLR4/NF-kappaB/STAT3 Axis Attenuates Astrogliosis-Mediated Microglial Activation and Neurotoxicity. PG - 2027-43 LID - 10.1523/JNEUROSCI.3457-15.2016 [doi] AB - 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-kappaB (NF-kappaB)- and interleukin-6/signal transducer and activator of transcription 3 (STAT3)-dependent transcriptional activation. The overexpression of the PKC phosphorylation-mimicking GAP43(S41D) (constitutive active GAP43) in astrocytes mimicked LPS-induced process arborization and elongation, while application of a NF-kappaB inhibitory peptide TAT-NBD or GAP43(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. SIGNIFICANCE STATEMENT: Astrogliosis is a complex state in which injury-stimulated astrocytes exert both protective and harmful effects on neuronal survival and plasticity. In this study, we demonstrated for the first time that growth-associated protein 43 (GAP43), a well known growth cone protein that promotes axonal regeneration, can be induced in rat brain astrocytes by the proinflammatory endotoxin lipopolysaccharide via both nuclear factor-kappaB and signal transducer and activator of transcription 3-mediated transcriptional activation. Importantly, LPS-induced GAP43 mediates plastic changes of astrocytes while attenuating astrogliosis-induced microglial activation and neurotoxicity. Hence, astrocytic GAP43 upregulation may serve to indicate beneficial astrogliosis after CNS injury. CI - Copyright (c) 2016 the authors 0270-6474/16/362028-17$15.00/0. FAU - Hung, Chia-Chi AU - Hung CC AD - Graduate Institute of Medical Sciences and Departments of Physiology and Department and Institute of Physiology, College of Medicine. FAU - Lin, Chun-Hua AU - Lin CH AD - Department of Nursing, Kang-Ning University, Taipei 114, Taiwan. FAU - Chang, Hsuan AU - Chang H AD - Department and Institute of Physiology, College of Medicine. FAU - Wang, Chen-Yu AU - Wang CY AUID- ORCID: 0000-0002-5659-2207 AD - Department and Institute of Physiology, College of Medicine, Brain Research Center, and. FAU - Lin, Shang-Hsuan AU - Lin SH AD - Department and Institute of Physiology, College of Medicine. FAU - Hsu, Pei-Chien AU - Hsu PC AD - Department and Institute of Physiology, College of Medicine, Brain Research Center, and. FAU - Sun, Yu-Yo AU - Sun YY AD - Department of Pediatrics, Division of Neurology, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia 30322. FAU - Lin, Teng-Nan AU - Lin TN AD - Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, and. FAU - Shie, Feng-Shiun AU - Shie FS AD - Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County 350, Taiwan. FAU - Kao, Lung-Sen AU - Kao LS AD - Brain Research Center, and Department of Life Sciences, Institute of Genomic Sciences, National Yang-Ming University, Taipei 112, Taiwan. FAU - Chou, Chih-Ming AU - Chou CM AD - Graduate Institute of Medical Sciences and Biochemistry and Molecular Cell Biology, College of Medicine, Taipei Medical University, Taipei 110, Taiwan. FAU - Lee, Yi-Hsuan AU - Lee YH AUID- ORCID: 0000-0002-3213-827X AD - Graduate Institute of Medical Sciences and Departments of Physiology and Department and Institute of Physiology, College of Medicine, Brain Research Center, and yhlee3@ym.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Cytokines) RN - 0 (Excitatory Amino Acid Transporter 2) RN - 0 (GAP-43 Protein) RN - 0 (Mrtfa protein, rat) RN - 0 (NF-kappa B) RN - 0 (STAT3 Transcription Factor) RN - 0 (Slc1a2 protein, rat) RN - 0 (Stat3 protein, rat) RN - 0 (Tlr4 protein, rat) RN - 0 (Toll-Like Receptor 4) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) SB - IM MH - Animals MH - Astrocytes/*drug effects MH - Cytokines/biosynthesis MH - Excitatory Amino Acid Transporter 2/biosynthesis/genetics MH - GAP-43 Protein/*biosynthesis/*genetics MH - Gliosis/*genetics MH - Macrophage Activation/drug effects MH - Microglia/*drug effects MH - NF-kappa B/*genetics MH - Neurons MH - Neurotoxicity Syndromes/*genetics/*pathology MH - Phosphorylation MH - Rats MH - Rats, Sprague-Dawley MH - STAT3 Transcription Factor/*genetics MH - Toll-Like Receptor 4/*genetics MH - Trans-Activators/biosynthesis/genetics MH - Transcription Factors PMC - PMC6602016 OTO - NOTNLM OT - EAAT2 OT - GAP43 OT - MKL1 OT - astrogliosis OT - microglial activation OT - neurotoxicity EDAT- 2016/02/13 06:00 MHDA- 2016/07/02 06:00 PMCR- 2016/08/10 CRDT- 2016/02/12 06:00 PHST- 2016/02/12 06:00 [entrez] PHST- 2016/02/13 06:00 [pubmed] PHST- 2016/07/02 06:00 [medline] PHST- 2016/08/10 00:00 [pmc-release] AID - 36/6/2027 [pii] AID - 3457-15 [pii] AID - 10.1523/JNEUROSCI.3457-15.2016 [doi] PST - ppublish SO - J Neurosci. 2016 Feb 10;36(6):2027-43. doi: 10.1523/JNEUROSCI.3457-15.2016.