Hippocampal multi-layered RNAseq prioritizes oligodendrocyte dysfunction over immune-driven neuroinflammation in neurolupus pathogenesis

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe manifestation of lupus marked by cognitive and mood disorders, yet its hippocampal molecular underpinnings remain poorly understood. Here, we provide a region-specific transcriptomic map of the hippocampus in MRL/Lpr mice --a validated NPSLE model-- compared to MRL+/+ controls. Bulk RNA-seq combined with integrative analyses (e.g. differential expression, GSEA, WGCNA, cell-type deconvolution) uncovered a robust disease-specific signature centered on oligodendrocyte dysfunction and myelination failure. Key myelin-related genes (Mbp, Plp1, Mog) and lineage-defining transcription factors (Sox10, Nkx6-2, Olig2) were repressed, while OPC markers remained unchanged, indicating a maturation blockade rather than lineage loss. Gene set enrichment highlighted widespread suppression of oligodendrocyte differentiation, axon ensheathment, and Wnt/retinoic acid signaling, alongside dysregulation of extracellular matrix components critical for axo-glial interactions. Co-expression network analysis revealed a disease-associated module enriched in myelination programs, with hub genes spanning structural, transcriptional, and adhesion-related functions. Deconvolution analysis confirmed a selective reduction of mature oligodendrocytes, contrasting with preserved neuronal populations and absence of classical astroglial or microglial activation signatures. RT-qPCR and Western blot validated the repression of myelination pathways at both mRNA and protein levels. Collectively, these findings challenge the inflammation-centric paradigm of NPSLE, revealing a cell-intrinsic vulnerability of the oligodendrocyte lineage. This conceptual shift -- from immune-driven damage to impaired glial development-- redefines NPSLE pathogenesis and suggests novel therapeutic avenues targeting oligodendrocyte maturation and remyelination rather than focusing solely on immunosuppression.