2. Academic Validation
  3. Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis

Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis

  • Mol Ther. 2021 Sep 1;29(9):2873-2885. doi: 10.1016/j.ymthe.2021.04.025.
Jian Chen 1,  Jiali Jin 1,  Xi Zhang 1,  Hailong Yu 1,  Xiaolei Zhu 1,  Linjie Yu 1,  Yanting Chen 1,  Pinyi Liu 1,  Xiaohong Dong 1,  Xiang Cao 1,  Yue Gu 1,  Xinyu Bao 1,  Shengnan Xia 1,  Yun Xu 2
Affiliations

Affiliations

  • 1 Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210008, P.R. China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, P.R. China; Nanjing Neurology Clinic Medical Center, Nanjing, Jiangsu 210008, P.R. China.
  • 2 Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210008, P.R. China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210093, P.R. China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, P.R. China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, P.R. China; Nanjing Neurology Clinic Medical Center, Nanjing, Jiangsu 210008, P.R. China. Electronic address: [email protected].
PMID: 33895326 DOI: 10.1016/j.ymthe.2021.04.025
Abstract

Dysregulated long non-coding RNAs (lncRNAs) have been shown to contribute to the pathogenesis of ischemic stroke. However, the potential role of lncRNAs in post-stroke microglial activation remains largely unknown. Here, we uncovered that lncRNA-U90926 was significantly increased in microglia exposed to ischemia/reperfusion both in vivo and in vitro. In addition, adenovirus-associated virus (AAV)-mediated microglial U90926 silencing alleviated neurological deficits and reduced infarct volume in experimental stroke mice. Microglial U90926 knockdown could reduce the infiltration of neutrophils into ischemic lesion site, which might be attributed to the downregulation of C-X-C motif ligand 2 (CXCL2). Mechanistically, U90926 directly bound to malate dehydrogenase 2 (MDH2) and competitively inhibited the binding of MDH2 to the CXCL2 3' untranslated region (UTR), thus protecting against MDH2-mediated decay of CXCL2 mRNA. Taken together, our study demonstrated that microglial U90926 aggravated ischemic brain injury via facilitating neutrophil infiltration, suggesting that U90926 might be a potential biomarker and therapeutic target for ischemic stroke.

Keywords

CXCL2; MDH2; U90926; ischemic stroke; microglia; neutrophil.

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