Background

The role of microglial CD85k in multiple sclerosis (MS) remains unclear. We investigated its function in autoimmune demyelination, focusing on lipid efflux and potential clinical relevance.

Methods

Single-cell profiling characterized CD85k expression in experimental autoimmune encephalomyelitis (EAE). A Cx3cr1-CreERT2-based conditional knockout model was used to investigate microglial CD85k function. CD85k expression in peripheral blood mononuclear cells (PBMCs) was compared between patients with MS and healthy controls, and its association with Expanded Disability Status Scale (EDSS) scores was assessed in patients. The apolipoprotein E-mimetic peptide COG1410 was administered intravenously via the tail vein before EAE onset. Clinical severity, spinal cord demyelination, central nervous system (CNS) immune-cell infiltration, and microglial lipid efflux were assessed. Transcriptomic analyses explored associated mechanisms.

Results

CD85k expression was significantly increased in EAE, with predominant expression in CNS microglia. Conditional deletion increased EAE clinical scores and exacerbated spinal cord demyelination. Patients with MS exhibited higher PBMC CD85k expression than healthy controls, and expression levels correlated positively with EDSS scores. Pre-onset COG1410 administration reduced clinical severity, spinal cord demyelination, and CNS immune-cell infiltration while enhancing microglial lipid efflux. Transcriptomic analyses linked CD85k to lipid transport pathways involving ABCA1 and ABCG1 and to the regulation of inflammatory responses.

Conclusions

These findings support a protective role for CD85k in autoimmune neuroinflammation and suggest that CD85k and its associated lipid efflux pathways warrant further investigation as therapeutic targets for MS.

Keywords: Multiple sclerosis; CD85k; Microglia; Lipid efflux; Neuroinflammation