Title : Neuroprotective effects of vesatolimod in EAE: Modulating immune balance and microglial polarization
Abstract:
Multiple Sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination and neuronal damage within the Central Nervous System (CNS), driven by pathogenic inflammatory immune cells. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model that recapitulates key aspects of MS pathology. Vesatolimod (VES), a TLR7 receptor agonist with antiviral properties, has previously demonstrated efficacy in reducing EAE symptoms, though its mechanisms of action remain unclear. Observing notable improvements in microglial behavior in prior studies, we focused on elucidating the underlying therapeutic mechanisms of VES in EAE, particularly its effects on microglial activation.
Methods: EAE was induced in mice using MOG35-55 and pertussis toxin, with daily clinical monitoring. Vesatolimod was administered at the onset of EAE symptoms in the treatment group. Outcome measures included assessments of disease progression, demyelination, Blood-Brain Barrier (BBB) integrity, T cell differentiation (Th1/Th17), CNS inflammatory infiltration, microglial activation and OLINK quantitative proteomics.
Results: VES treatment significantly mitigated clinical symptoms and disease severity in EAE, with improvements in BBB integrity and a reduction in spinal cord demyelination. Flow cytometry of blood and spleen samples revealed that VES increased regulatory T cell populations while inhibiting IFNγ+ and IL17A+ lymphocytes. Fluorescent staining of spinal cord tissue demonstrated that VES reduced microglial differentiation into M1 and M2 subtypes. Further mechanistic analyses indicated that VES’s protective effects may be mediated through the Nrf2/HO-1 signaling pathway.
Conclusion: These findings suggest that Vesatolimod exerts therapeutic effects in EAE by modulating immune responses, enhancing BBB integrity, and regulating microglial activation via the Nrf2/HO-1 pathway. This study underscores the potential of VES as a novel therapeutic approach for MS treatment.
