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

• Published in: Journal of neuroimmune pharmacology Vol. 19; no. 1; p. 11
• Main Authors: Pan, Hung-Chuan, Yang, Cheng-Ning, Lee, Wen-Jane, Sheehan, Jason, Wu, Sheng-Mao, Chen, Hong-Shiu, Lin, Mao-Hsun, Shen, Li-Wei, Lee, Shu-Hua, Shen, Chin-Chang, Pan, Liang-Yi, Liu, Shing‑Hwa, Sheu, Meei-Ling
• Format: Journal Article
• Language: English
• Published: New York Springer US 26.03.2024; Springer Nature B.V
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cell Biology; Correspondence; Genotype & phenotype; Immunology; Inflammation; Inflammation - metabolism; Lipopolysaccharides - pharmacology; Melatonin; Melatonin - pharmacology; Mice; Microglia; Molecular Docking Simulation; Neurosciences; Pharmacology/Toxicology; PPAR delta - metabolism; PPAR delta - pharmacology; PPAR delta - therapeutic use; Rats; Sirtuin 1 - metabolism; Virology; Melatonin; Microglia, Neuro-inflammation; SIRT1; PPARδ
• ISSN: 1557-1904; 1557-1890; 1557-1904
• DOI: 10.1007/s11481-024-10108-y

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