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Inhibition of Dyrk1A Attenuates LPS-Induced Neuroinflammation via the TLR4/NF-κB P65 Signaling Pathway

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Abstract

Dual-specificity tyrosine phosphorylation–regulated kinase 1A (Dyrk1A) is a highly conserved protein kinase, playing a key role in the regulation of physiological brain functions and pathological processes. In Alzheimer’s disease (AD), Dyrk1A promotes hyperphosphorylation of tau protein and abnormal aggregation of amyloid-β protein (Aβ). This study investigated the role of Dyrk1A in regulating neuroinflammation, another critical factor that contributes to AD. In the present study, we used an immortalized murine BV2 microglia cell line induced by lipopolysaccharide (LPS) to study neuroinflammation. The expression and activity of Dyrk1A kinase were both increased by inflammation. Dyrk1A inhibition using harmine or siRNA silencing significantly reduced the production of proinflammatory factors in LPS-stimulated BV2 cells. Reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), as well as the expression of the inflammatory proteins, cyclooxygenase 2 (COX2), and inducible nitric synthase (iNOS), were attenuated. In vivo, in ICR mice injected with LPS into the left lateral cerebral ventricle, harmine (20 mg/kg) administration decreased the expression of inflammatory proteins in the cortex and hippocampus of mice brain. In addition, immunohistochemical detection of ionized calcium-binding adapter molecule 1 (Iba1) and Nissl staining showed that harmine significantly attenuated microglia activation and neuronal damage in the CA1 region of hippocampus. Further mechanistic studies indicated that Dyrk1A suppression may be related to inhibition of the TLR4/NF-κB signaling pathway in LPS-induced neuroinflammation. Taken together, our studies suggest that Dyrk1A may be a novel target for the treatment of neurodegenerative diseases with an inflammatory component.

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Funding

This study was financially supported by grants from the National Sciences Foundation of China (81630097, 81773718, 81773589), The National Key Research and Development Program of China (Grant No. SQ2018YFA090025-04 and No. 2018YFA0901900), CAMS Innovation Fund for Medical Sciences (2021-1012 M-028 and 2021-I2M-1–028), The Drug Innovation Major Project (2018ZX09711001-003–020, 2018ZX09711001-003–005, and 2018ZX09711001-008–005), and CAMS The Fundamental Research Funds for the Central Universities (2018RC350002).

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Authors and Affiliations

  1. State Key Laboratory of Bioactive Substrate and Function of Natural Medicine, Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Xian Nong Tan Street, Beijing, 100050, China

    Cheng Ju, Yue Wang, Caixia Zang, Hui Liu, Fangyu Yuan, Jingwen Ning, Meiyu Shang, Jingwei Ma, Gen Li, Yang Yang, Xiuqi Bao & Dan Zhang

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  1. Cheng Ju
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  2. Yue Wang
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  3. Caixia Zang
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  4. Hui Liu
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  9. Gen Li
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  10. Yang Yang
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  11. Xiuqi Bao
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  12. Dan Zhang
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Contributions

Dan Zhang and Xiuqi Bao revised the manuscript and advised experimental design; Cheng Ju wrote the manuscript; Cheng Ju and Yue Wang performed the research; Caixia Zang and Hui Liu conducted and helped with the experiment methods; Fangyu Yuan, Jingwen Ning, and Meiyu Shang analyzed the data and participated in statistical analyses; Jingwei Ma, Gen Li, and Yang Yang were responsible for surgery and treatments. All of the authors read and approved the final manuscript.

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Correspondence to Dan Zhang.

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All animal studies were approved by the Animal Care and Welfare Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College.

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Authors Cheng Ju and Yue Wang contributed equally to this article.

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Ju, C., Wang, Y., Zang, C. et al. Inhibition of Dyrk1A Attenuates LPS-Induced Neuroinflammation via the TLR4/NF-κB P65 Signaling Pathway. Inflammation 45, 2375–2387 (2022). https://doi.org/10.1007/s10753-022-01699-w

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