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Microglial lnc-U90926 facilitates neutrophil infiltration in ischemic stroke via MDH2/CXCL2 axis
Jian Chen1, Jiali Jin1, Xi Zhang1
1Department 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.
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.
Insights
Long non-coding RNA U90926 promotes ischemic stroke injury by increasing neutrophil infiltration. Silencing this long non-coding RNA (lncRNA) in microglia reduces brain damage, suggesting it as a therapeutic target.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Long non-coding RNAs (lncRNAs) are implicated in ischemic stroke pathogenesis.
- The role of lncRNAs in post-stroke microglial activation is not well understood.
Purpose of the Study:
- Investigate the role of lncRNA-U90926 in microglial activation following ischemic stroke.
- Determine if targeting lncRNA-U90926 can mitigate ischemic brain injury.
Main Methods:
- Measured U90926 levels in microglia under ischemia/reperfusion (in vivo and in vitro).
- Utilized adenovirus-associated virus (AAV) to silence U90926 in microglia in a mouse stroke model.
- Assessed neurological deficits, infarct volume, and neutrophil infiltration.
- Investigated the molecular mechanism involving malate dehydrogenase 2 (MDH2) and C-X-C motif ligand 2 (CXCL2).
Main Results:
- U90926 expression was significantly increased in microglia after ischemia/reperfusion.
- AAV-mediated U90926 silencing reduced neurological deficits and infarct volume.
- Knockdown of U90926 decreased neutrophil infiltration, linked to CXCL2 downregulation.
- U90926 was found to bind MDH2, inhibiting MDH2's decay of CXCL2 mRNA.
Conclusions:
- Microglial U90926 exacerbates ischemic brain injury by promoting neutrophil infiltration.
- U90926 may serve as a potential biomarker and therapeutic target for ischemic stroke.
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