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Regulatory Effects of Neuroinflammatory Responses Through Brain-Derived Neurotrophic Factor Signaling in Microglial Cells

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Abstract

Inhibition of microglial over-activation is an important strategy to counter balance neurodegenerative progression. We previously demonstrated that the adenosine monophosphate-activated protein kinase (AMPK) may be a therapeutic target in mediating anti-neuroinflammatory responses in microglia. Brain-derived neurotrophic factor (BDNF) is one of the major neurotrophic factors produced by astrocytes to maintain the development and survival of neurons in the brain, and have recently been shown to modulate homeostasis of neuroinflammation. Therefore, the present study focused on BDNF-mediated neuroinflammatory responses and may provide an endogenous regulation of neuroinflammation. Among the tested neuroinflammation, epigallocatechin gallate (EGCG) and minocycline exerted BDNF upregulation to inhibit COX-2 and proinflammatory mediator expressions. Furthermore, both EGCG and minocycline upregulated BDNF expression in microglia through AMPK signaling. In addition, minocycline and EGCG also increased expressions of erythropoietin (EPO) and sonic hedgehog (Shh). In the endogenous modulation of neuroinflammation, astrocyte-conditioned medium (AgCM) also decreased the expression of COX-2 and upregulated BDNF expression in microglia. The anti-inflammatory effects of BDNF were mediated through EPO/Shh in microglia. Our results indicated that the BDNF-EPO-Shh novel-signaling pathway underlies the regulation of inflammatory responses and may be regarded as a potential therapeutic target in neurodegenerative diseases. This study also reveals a better understanding of an endogenous crosstalk between astrocytes and microglia to regulate anti-inflammatory actions, which could provide a novel strategy for the treatment of neuroinflammation and neurodegenerative diseases.

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Funding

This work is supported in part by grants from the Ministry of Science and Technology (102-2320-B-039-026-MY3 and 105-2320-B-039-058-), China Medical University (CMU102-ASIA-24 and CMU103-ASIA-02), Taichung Tzu Chi Hospital (TTCRD104-13 and TTCRD102-11), and Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW106-TDU-B-212-113004).

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  1. Sheng-Wei Lai and Jia-Hong Chen contributed equally to this work.

Authors and Affiliations

  1. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan

    Sheng-Wei Lai

  2. Department of General Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan

    Jia-Hong Chen

  3. School of Medicine, Tzu Chi University, Hualien, Taiwan

    Jia-Hong Chen

  4. Department of Pharmacology, School of Medicine, China Medical University, No.91 Hsueh-Shih Road, Taichung, Taiwan

    Hsiao-Yun Lin, Yu-Shu Liu & Dah-Yuu Lu

  5. Department of Biotechnology, Asia University, Taichung, Taiwan

    Yu-Shu Liu & Cheng-Fang Tsai

  6. Department of Bioinformatics, Asia University, Taichung, Taiwan

    Pei-Chun Chang

  7. Department of Photonics and Communication Engineering, Asia University, Taichung, Taiwan

    Dah-Yuu Lu

  8. Department of Physiology, School of Medicine, China Medical University, Taichung, Taiwan

    Chingju Lin

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  1. Sheng-Wei Lai
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Correspondence to Dah-Yuu Lu or Chingju Lin.

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Lai, SW., Chen, JH., Lin, HY. et al. Regulatory Effects of Neuroinflammatory Responses Through Brain-Derived Neurotrophic Factor Signaling in Microglial Cells. Mol Neurobiol 55, 7487–7499 (2018). https://doi.org/10.1007/s12035-018-0933-z

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  • DOI: https://doi.org/10.1007/s12035-018-0933-z

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