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Melatonin Enhanced Microglia M2 Polarization in Rat Model of Neuro-inflammation Via Regulating ER Stress/PPARδ/SIRT1 Signaling Axis

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Abstract

Neuro-inflammation involves distinct alterations of microglial phenotypes, containing nocuous pro-inflammatory M1-phenotype and neuroprotective anti-inflammatory M-phenotype. Currently, there is no effective treatment for modulating such alterations. M1/M2 marker of primary microglia influenced by Melatonin were detected via qPCR. Functional activities were explored by western blotting, luciferase activity, EMSA, and ChIP assay. Structure interaction was assessed by molecular docking and LIGPLOT analysis. ER-stress detection was examined by ultrastructure TEM, calapin activity, and ERSE assay. The functional neurobehavioral evaluations were used for investigation of Melatonin on the neuroinflammation in vivo. Melatonin had targeted on Peroxisome Proliferator Activated Receptor Delta (PPARδ) activity, boosted LPS-stimulated alterations in polarization from the M1 to the M2 phenotype, and thereby inhibited NFκB–IKKβ activation in primary microglia. The PPARδ agonist L-165,041 or over-expression of PPARδ plasmid (ov-PPARδ) showed similar results. Molecular docking screening, dynamic simulation approaches, and biological studies of Melatonin showed that the activated site was located at PPARδ (phospho-Thr256-PPARδ). Activated microglia had lowered PPARδ activity as well as the downstream SIRT1 formation via enhancing ER-stress. Melatonin, PPARδ agonist and ov-PPARδ all effectively reversed the above-mentioned effects. Melatonin blocked ER-stress by regulating calapin activity and expression in LPS-activated microglia. Additionally, Melatonin or L-165,041 ameliorated the neurobehavioral deficits in LPS-aggravated neuroinflammatory mice through blocking microglia activities, and also promoted phenotype changes to M2-predominant microglia. Melatonin suppressed neuro-inflammation in vitro and in vivo by tuning microglial activation through the ER-stress-dependent PPARδ/SIRT1 signaling cascade. This treatment strategy is an encouraging pharmacological approach for the remedy of neuro-inflammation associated disorders.

Graphical Abstract

Schematic of Proposed Mechanism for the role of Melatonin in Activated Microglia and neuro-inflammation Effects. LPS-induced ER Stress and Regulated PPARδ Expression, NFκB Phosphorylation, Subsequently Reduces SIRT1 Expression and then Triggers the Microglia Activation and Brain Damage. In the Present Study, we Provide the Evidence to Demonstrate that Melatonin Plays a Potential Protective role in Neuroprotective Effects through PPARδ/SIRT1 Pathway. In Addition, PPARδ Pharmacological Agonists L165041 also Possessed Similar Effects. These Results Suggest that the Activation of PPARδ/SIRT1 by Melatonin could Counteract the Detrimental Effect of LPS. Also, the Results Suggest Melatonin may Exert a Therapeutic Effect for Neuroinflammatory Disorders

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Data Availability

The datasets applied during the current study are available on reasonable request. All data generated or analyzed during this study are included in this published article.

Abbreviations

ChIP:

Chromatin Immunoprecipitation Assay

ER Stress:

Endoplasmic Reticulum Stress

EMSA:

Electrophoretic Mobility Shift Assay

HFD:

High-Fat Diet

LPS:

Lipopolysaccharide

TEM:

Transmission Electron Microscope

ovPPAR:

δPPARδ plasmid

PPARδ:

Peroxisome Proliferator Activated Receptor Delta

PPRES:

PPAR Response Elements

qPCR:

Quantitative PCR

RXR:

Retinoic X Receptor

SIRT1:

Sirtuin 1

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Acknowledgements

The authors wish to thank Taichung Veterans General Hospital (TCVGH), particularly its Tissue Bank, and for its Animal Center Care. The authors also thank the National RNAi Core Facility Platform, Taipei, Taiwan for the shRNA and the Genome Research Center, National Yang-Ming University for the pcDNA.

Funding

This study was supported by grants from the Ministry of Science and Technology, the National Science Council, Taiwan (MOST-106-2320-B-005-001-MY3, MOST-104-2320-B-005-002-MY3), National Chung Hsing University, Taiwan (NCHU108ST001F), Taichung Veterans General Hospital in Taiwan (TCVGH-1087327D, TCVGH-1087308 C, TCVGH-1077311 C, TCVGH-1077329D) and Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan. The study was partially supported by the framework of the Higher Education Sprout Project from the Ministry of Education (MOE-112-S-0023-A) in Taiwan.

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Author notes

  1. Hong-Shiu Chen and Mao-Hsun Lin contributed equally to first author.

  2. Shing‑Hwa Liu contributed equally to corresponding author.

Authors and Affiliations

  1. Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan

    Hung-Chuan Pan

  2. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan

    Hung-Chuan Pan, Wen-Jane Lee & Meei-Ling Sheu

  3. Ph.D. Program in Translational Medicine, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan

    Hung-Chuan Pan & Meei-Ling Sheu

  4. Doctoral Program in Biotechnology Industrial Management and Innovation, National Chung Hsing University, Taichung, Taiwan

    Hung-Chuan Pan

  5. College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan, Taiwan

    Hung-Chuan Pan

  6. Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan

    Cheng-Ning Yang

  7. Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA

    Jason Sheehan

  8. Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan

    Sheng-Mao Wu, Li-Wei Shen, Shu-Hua Lee & Meei-Ling Sheu

  9. Department of Neurosurgery, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan

    Hong-Shiu Chen

  10. Division of Neurology, Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan

    Mao-Hsun Lin

  11. Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan

    Chin-Chang Shen

  12. School of Medicine, Kaohsiung Medical University, Taichung, Taiwan

    Liang-Yi Pan

  13. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan

    Shing‑Hwa Liu

  14. Institute of Biomedical Sciences, College of Life Sciences, National Chung Hsing University, 250, Kuo Kuang Road, Taichung, 402, Taiwan

    Meei-Ling Sheu

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  1. Hung-Chuan Pan
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Contributions

Pan HC, Wu SM and Sheu ML performed all of the mouse and cellular experiments, and generated and analyzed data; Yang CN, Pan LY for primary all of mouse primary microglia and BV2 microglia. Lee WJ, Sheehan J consulted and analyzed the data. Pan HC, Lin MH and Chen HS provide clinical information. Lee SH participated in immunofluorescence image experiments. Shen CC, Shen LW conducting molecular docking studies and LIGPLOT. Sheu ML directed the experiments and analyzed and assembled the data. All authors approved the final manuscript.

Corresponding author

Correspondence to Meei-Ling Sheu.

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Ethics Approval and Consent to Participate

All animal studies were approved by the appropriate institutional ethical committee of the Taichung Veterans General Hospital of Taiwan (Approval No La-1061488). All procedures have been conformed according to the guidelines from the NIH Guide for the Care and Use of Laboratory Animals. All animals were euthanized by cervical dislocation under isoflurane inhalation (induction: 3%, maintenance: 1–2%) in medical air (0.4 L/min). Consent to participate-NA/Not applicable.

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The authors declare no competing interests.

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Pan, HC., Yang, CN., Lee, WJ. et al. Melatonin Enhanced Microglia M2 Polarization in Rat Model of Neuro-inflammation Via Regulating ER Stress/PPARδ/SIRT1 Signaling Axis. J Neuroimmune Pharmacol 19, 11 (2024). https://doi.org/10.1007/s11481-024-10108-y

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