Uncovering immune characteristics of neurons in the context of multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an immune-mediated disease characterized by chronic inflammation and damage to the central nervous system, and substantial characterization of molecular signatures of glial and immune cells in the disease has been conducted. However, comparatively less well characterized is the molecular signature of pathologically inflamed neurons. Here, we accessed multi-omic high-throughput transcriptomic and epigenomic data to investigate the molecular signature of neurons from progressive MS patients and from mice subjected to experimental autoimmune encephalomyelitis (EAE). Our results indicate a shared and consistent neuronal gene expression signature in MS and EAE samples including a notable upregulation of immune system related genes and processes. Analysis of immune-enriched pathways in retinal ganglion cells (RGCs) and motor neurons from mice subjected to EAE revealed enrichment for the major histocompatibility complex class I pathway and interferon response genes in both types of neurons, and ATAC-seq analysis confirmed the accessibility of these genes. Parallel analyses of neurons from MS patients identified a signature of 48 commonly upregulated immune genes in neurons. Prediction of transcriptional regulators of these genes identified key upstream regulators including signal transducer and activation of transcription 1 (STAT1) and interferon response factor 5 (IRF5), highly involved in immune-related processes, with significant gene expression changes in both RGCs and motor neurons. Protein-protein interaction analyses among the transcriptional regulators unveiled intricate interactions among transcription factors, especially from the IRF and STAT families, suggesting their importance in regulating immune gene expression in inflamed neurons. Small molecule inhibition of IRF5 in inflamed neurons in vitro promoted cell survival and reduced the expression of the immune gene signature, supporting the biological relevance of IRF5 in mediating the neuronal inflammatory response. Together, this study identifies regulated immune processes in neurons from EAE mice and from MS patient samples suggesting potential roles for neuronal immune molecules in disease progression, as revealed by transcriptomic, epigenomic, and experimental approaches. Further, the results strongly implicate active interferon signaling in neurons driving immune related changes in gene expression through IRF5 and STAT1 transcription factor activity, potentially impacting downstream neuronal survival through IRF5 activity.