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Single-Cell Profiling Reveals Mediators of Immune-Vascular Crosstalk in Mouse Models of Relapsing and Progressive Multiple Sclerosis

ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) with heterogeneous clinical courses. While current therapies can modulate the immune system, their efficacy in halting progressive neurodegeneration remains limited, underscoring the need for novel interventions that address both immune and vascular dysfunction. To investigate the mechanisms underlying these processes, we employed the myelin oligodendrocyte glycoprotein (MOG₃₅–₅₅)-induced experimental autoimmune encephalomyelitis (EAE) model, utilizing C57BL/6 mice, which develop a relapsing-remitting MS-like course, and NOD/ShiLtJ mice, which exhibit a secondary-progressive MS-like course. We performed single-cell RNA sequencing (scRNA-seq) on lumbar spinal cord tissues from these EAE models at the disease peak. Our analysis revealed distinct, cell-type-specific transcriptomic landscapes associated with relapsing and progressive pathologies. We identified critical mediators of immune-vascular crosstalk that were dysregulated across both disease phases, pinpointing conserved pathways and cell populations involved in disease perpetuation. Functional validation confirmed that targeting these key pathways can suppress pro-inflammatory immune cell activity, restore vascular integrity, and ameliorate clinical symptoms in both EAE models. This study provides a high-resolution resource of the immune and vascular interactions in relapsing and progressive MS models. Our findings uncover novel mechanisms sustaining neuroinflammation and highlight promising therapeutic targets for modulating both relapsing and progressive forms of MS.

ORGANISM(S): Mus musculus

PROVIDER: GSE312491 | GEO | 2026/04/22

REPOSITORIES: GEO

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Project description:Chronic innate immune activation in the central nervous system (CNS) significantly contributes to neurodegeneration in progressive multiple sclerosis (MS). Using multiple EAE models, we explored the potential of the innate immune sensor NLRX1 to protect neurons in the anterior visual pathway from inflammatory neurodegeneration. To do this, we assessed retinal ganglion cell (RGC) density and optic nerve axonal degeneration, gliosis, and T-cell infiltration in Nlrx1-/- and wild-type (WT) EAE mice. Our results indicate that Nlrx1-/- mice exhibit significantly increased RGC loss and axonal injury compared to WT mice in both active immunization EAE and spontaneous opticospinal encephalomyelitis models. Adoptive transfer experiments, in which wild type T cells were transferred into lymphocyte-deficient Rag-/- mice to minimize the effects of Nlrx1 knockout on peripheral lymphocyte priming, revealed more severe microgliosis and astrogliosis in the optic nerve of Nlrx1-/-Rag-/- mice compared to Rag-/- mice, suggesting a regulatory role of NLRX1 in innate immune compartments. Transcriptome analysis in primary astrocytes demonstrated that NLRX1 negatively regulates TLR-mediated NF-κB activation. The novel pharmacologic NLRX1 activator LABP-66 decreased LPS-mediated gene expression of inflammatory cytokines and chemokines in mixed glial cultures. Moreover, treating EAE mice with oral LABP-66 after the onset of paralysis resulted in less anterior visual pathway neurodegeneration compared to vehicle. These data suggest that a pharmacologic NLRX1 activators attenuates glial immune activation and has the potential to limit inflammatory neurodegeneration in diseases, such as MS, where chronic CNS-compartmentalized inflammation may drive neurodegenerative pathology. This study highlights that NLRX1 could serve as a promising target for neuroprotection in progressive MS and other neurodegenerative diseases where chronic compartmentalized innate immune activation and neuroinflammation play a role.

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Single-Cell Profiling Reveals Mediators of Immune-Vascular Crosstalk in Mouse Models of Relapsing and Progressive Multiple Sclerosis

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