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IL-9-triggered lncRNA Gm13568 regulates Notch1 in astrocytes through interaction with CBP/P300: contribute to the pathogenesis of experimental autoimmune encephalomyelitis

Authors
  • Liu, Xiaomei1
  • Zhou, Feng1
  • Wang, Weixiao1
  • Chen, Guofang2, 3, 4
  • Zhang, Qingxiu5
  • Lv, Ruixue1
  • Zhao, Zijun1
  • Li, Xiangyang1
  • Yu, Qian1
  • Meves, Jessica M.6
  • Hua, Hui1
  • Li, Xiaocui1
  • Wang, Xiaotian1
  • Sun, Hong7
  • Gao, Dianshuai7
  • 1 Xuzhou Medical University, 209 Tongshan Road, Xuzhou, Jiangsu, 221004, People’s Republic of China , Xuzhou (China)
  • 2 The Affiliated Xuzhou Center Hospital of Nanjing University of Chinese Medicine, Xuzhou, People’s Republic of China , Xuzhou (China)
  • 3 Xuzhou Central Hospital, Xuzhou, People’s Republic of China , Xuzhou (China)
  • 4 Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, Jiangsu, 221009, People’s Republic of China , Xuzhou (China)
  • 5 Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, People’s Republic of China , Xuzhou (China)
  • 6 University of Michigan Medicine, MI48109, Ann Arbor, Michigan, USA , Ann Arbor (United States)
  • 7 Xuzhou Medical University, Xuzhou, Jiangsu, 221004, People’s Republic of China , Xuzhou (China)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
May 11, 2021
Volume
18
Issue
1
Identifiers
DOI: 10.1186/s12974-021-02156-5
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundInterleukin 9 (IL-9), produced mainly by T helper 9 (Th9) cells, has been recognized as an important regulator in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Astrocytes respond to IL-9 and reactive astrocytes always associate with blood-brain barrier damage, immune cell infiltration, and spinal injury in MS and EAE. Several long non-coding RNAs (lncRNAs) with aberrant expression have been identified in the pathogenesis of MS. Here, we examined the effects of lncRNA Gm13568 (a co-upregulated lncRNA both in EAE mice and in mouse primary astrocytes activated by IL-9) on the activation of astrocytes and the process of EAE.MethodsIn vitro, shRNA-recombinant lentivirus with glial fibrillary acidic protein (GFAP) promoter were performed to determine the relative gene expression and proinflammatory cytokines production in IL-9 treated-astrocytes using Western blot, real-time PCR, and Cytometric Bead Array, respectively. RIP and ChIP assays were analyzed for the mechanism of lncRNA Gm13568 regulating gene expression. Immunofluorescence assays was performed to measure the protein expression in astrocytes. In vivo, H&E staining and LFB staining were applied to detect the inflammatory cells infiltrations and the medullary sheath damage in spinal cords of EAE mice infected by the recombinant lentivirus. Results were analyzed by one-way ANOVA or Student’s t test, as appropriate.ResultsKnockdown of the endogenous lncRNA Gm13568 remarkably inhibits the Notch1 expression, astrocytosis, and the phosphorylation of signal transducer and activator of transcription 3 (p-STAT3) as well as the production of inflammatory cytokines and chemokines (IL-6, TNF-α, IP-10) in IL-9-activated astrocytes, in which Gm13568 associates with the transcriptional co-activators CBP/P300 which are enriched in the promoter of Notch1 genes. More importantly, inhibiting Gm13568 with lentiviral vector in astrocytes ameliorates significantly inflammation and demyelination in EAE mice, therefore delaying the EAE process.ConclusionsThese findings uncover that Gm13568 regulates the production of inflammatory cytokines in active astrocytes and affects the pathogenesis of EAE through the Notch1/STAT3 pathway. LncRNA Gm13568 may be a promising target for treating MS and demyelinating diseases.

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