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Author Spotlight: Unveiling the Pathway Linking Obesity to Autoimmune Inflammation in Multiple Sclerosis
Published on: February 23, 2024
Morroniside ameliorates experimental autoimmune encephalomyelitis by regulating gut microenvironment, immune balance,
Taotao Jiang1, Shaopeng Zhai1, Ting Zheng1
1The Department of Neurology, The Second Hospital of Lanzhou University, Lanzhou, 730030, China.
Abstract:
Multiple sclerosis (MS) is a chronic disease characterized by demyelination and neuroinflammation in the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is a classic animal model for MS. Existing therapeutic drugs for MS have limitations such as high cost, significant side effects, and the inability to reverse nerve damage. Morroniside, as a natural iridoid glycoside compound, has anti-inflammatory and antioxidant activities, but its therapeutic mechanism in MS remains unclear. Morroniside significantly delayed the onset time of EAE mice, reduced the clinical symptom score, and improved the weight loss. DTI showed that it repaired the microstructure of the corpus callosum and cerebellum; decreased the values of ADC, MD, and RD; and increased the FA value. Histopathology confirmed that it reduced inflammatory infiltration and demyelination. Mechanistically, morroniside had the effects of improving peripheral immune balance and neuroinflammation. Flow cytometry showed that morroniside downregulated the proportions of Th1 and Th17 cells in the spleen and upregulated the proportion of Treg cells. RT-qPCR showed that morroniside inhibited the expressions of IL-1β, IL-6, and TNF-α in the brain and spinal cord tissue. Transcriptome analysis revealed that there were 30 overlapping differentially expressed genes among the differentially expressed genes in the EAE group versus the control group and the treatment group versus the EAE group. GO and KEGG pathway enrichment analyses found that the differentially expressed genes were significantly enriched in biological processes such as the inflammatory response and immune response, as well as signaling pathways such as NF-κB, PI3K-AKT, and NOD-like receptor. WB, RT-qPCR, and ELISA verified that morroniside could alleviate neuroinflammation by inhibiting the gene and protein expressions of Tnfsf8 and the NF-κB pathway. Molecular docking showed that morroniside had a good binding ability with Tnfsf8, with a binding energy of - 6.3 kcal/mol. In addition, morroniside also improved the gut microbiota dysbiosis in EAE mice. Although it failed to completely restore the level of the genus Lactobacillus, its regulatory effect on the gut microenvironment is worthy of further study. Morroniside improves the pathological process of EAE by multi-target regulation of the peripheral immune balance, inhibition of NF-κB-mediated neuroinflammation, and regulation of the gut microenvironment.
Insights
Morroniside, a natural compound, effectively treats experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS). It reduces inflammation and nerve damage by modulating immune cells and inhibiting the NF-κB pathway, offering a promising therapeutic avenue for MS.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a chronic central nervous system disease with limited treatment options.
- Experimental autoimmune encephalomyelitis (EAE) serves as a key animal model for studying MS pathogenesis.
- Current MS therapies face challenges including high costs, side effects, and inability to reverse neurological damage.
Purpose of the Study:
- To investigate the therapeutic potential and underlying mechanisms of morroniside in a mouse model of multiple sclerosis (EAE).
- To evaluate morroniside's effects on neuroinflammation, immune cell balance, and central nervous system microstructure.
- To elucidate the molecular targets and pathways modulated by morroniside in EAE.
Main Methods:
- Administration of morroniside to EAE mice, followed by clinical assessments and weight monitoring.
- Diffusion Tensor Imaging (DTI) to assess white matter integrity (corpus callosum, cerebellum).
- Histopathology, flow cytometry, RT-qPCR, transcriptome analysis, Western blot (WB), and ELISA to evaluate immune responses, gene/protein expression, and signaling pathways.
- Molecular docking to predict binding affinity between morroniside and target molecules.
- Gut microbiota analysis.
Main Results:
- Morroniside significantly delayed EAE onset, reduced clinical scores, and improved weight loss.
- DTI revealed microstructural repair in the corpus callosum and cerebellum, with altered ADC, MD, RD, and FA values.
- Histopathology confirmed reduced inflammatory infiltration and demyelination.
- Morroniside modulated peripheral immune balance by downregulating Th1/Th17 cells and upregulating Treg cells.
- Inhibition of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) and key pathway mediators (Tnfsf8, NF-κB) was observed.
- Transcriptome analysis identified differentially expressed genes enriched in inflammatory and immune response pathways, including NF-κB and PI3K-AKT.
- Molecular docking indicated strong binding of morroniside to Tnfsf8.
- Morroniside improved gut microbiota dysbiosis in EAE mice.
Conclusions:
- Morroniside demonstrates significant therapeutic effects in the EAE model, ameliorating clinical symptoms and neuropathology.
- Its mechanism involves multi-target regulation, including peripheral immune balance, inhibition of NF-κB-mediated neuroinflammation via Tnfsf8, and gut microbiota modulation.
- Morroniside represents a promising natural compound for further development as a treatment for multiple sclerosis.
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