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Published on: September 12, 2016
Temporin-GHaR6R Peptide Ameliorates Experimental Autoimmune Encephalomyelitis by Suppressing Microglial M1
Da-Qi Zhang1,2,3, Hui-Min Xu1, Jing Lu1
1Department of Neurology, the First Affiliated Hospital of Hainan Medical University, Haikou, 570102, China.
Abstract:
Multiple sclerosis (MS), an immune-mediated inflammatory demyelinating disorder of the central nervous system (CNS), is driven by microglia as key orchestrators of neuroinflammation. This study assessed the preventive potential of temporin-GHaR6R (GHaR6R), an antimicrobial peptide derived from Hylarana guentheri skin, using the experimental autoimmune encephalomyelitis (EAE) murine model of MS. Preventive administration of GHaR6R significantly reduced EAE incidence and alleviated clinical severity, while histopathological analyses (HE and LFB staining) revealed attenuated inflammatory cell infiltration and demyelination in the spinal cord. Mechanistically, GHaR6R suppressed M1 microglial polarization, thereby limiting excessive neuroinflammatory activation. In vitro, GHaR6R inhibited TNF-α and IL-6 secretion, reduced mitochondrial ROS production, preserved mitochondrial membrane potential in LPS-activated BV2 microglia, and promoted the shift from M1 to M2 microglial polarization. Consistent with these findings, GHaR6R downregulated mitochondrial fission protein Drp-1 while upregulating the fusion mediators MFN1 and MFN2 in both EAE-affected spinal cords and LPS-stimulated BV2 cells. Immunofluorescence analysis showed increased colocalization of Iba-1 with MFN1/2, indicating enhanced mitochondrial fusion in microglia. Taken together, these results demonstrate that GHaR6R ameliorates EAE progression by modulating microglial mitochondrial dynamics, mitigating neuroinflammation, and inhibiting M1 polarization, highlighting its potential as an early prophylactic intervention for MS.
Insights
Temporin-GHaR6R (GHaR6R) peptide prevents multiple sclerosis (MS) by reducing neuroinflammation. It modulates microglial mitochondrial dynamics, inhibiting M1 polarization and promoting M2, offering potential as an early MS prophylactic intervention.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a CNS inflammatory demyelinating disorder orchestrated by microglia.
- Microglial activation and neuroinflammation are key drivers of MS pathogenesis.
Purpose of the Study:
- To evaluate the preventive potential of temporin-GHaR6R (GHaR6R), an antimicrobial peptide, in a murine model of MS.
- To elucidate the underlying mechanisms of GHaR6R's therapeutic effects on microglial function and neuroinflammation.
Main Methods:
- Experimental autoimmune encephalomyelitis (EAE) murine model for MS.
- Histopathological analysis (HE, LFB staining) of spinal cords.
- In vitro studies using LPS-activated BV2 microglia.
- Assessment of microglial polarization (M1/M2 markers).
- Analysis of mitochondrial dynamics (ROS, membrane potential, fission/fusion proteins).
Main Results:
- Preventive GHaR6R administration significantly reduced EAE incidence and clinical severity.
- Histopathology showed decreased inflammation and demyelination in GHaR6R-treated mice.
- GHaR6R suppressed M1 microglial polarization, reduced pro-inflammatory cytokine secretion (TNF-α, IL-6), and decreased mitochondrial ROS production.
- GHaR6R preserved mitochondrial membrane potential and promoted mitochondrial fusion by upregulating MFN1/2 and downregulating Drp-1 in microglia.
Conclusions:
- GHaR6R ameliorates EAE progression by modulating microglial mitochondrial dynamics and mitigating neuroinflammation.
- GHaR6R inhibits M1 microglial polarization and promotes a shift towards M2 phenotype.
- These findings highlight GHaR6R's potential as an early prophylactic intervention for multiple sclerosis.
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