Distinctive transcriptomic and epigenomic signatures of bone marrow-derived myeloid cells and microglia in CNS autoimmunity

In the context of autoimmunity, myeloid cells of the central nervous system (CNS) constitute an ontogenically heterogeneous population that includes yolk sac-derived microglia and infiltrating bone marrow-derived cells (BMC). We previously identified a myeloid cell subset in the brain and spinal cord that expresses the surface markers CD88 and CD317 and is associated with the onset and persistence of clinical disease in the murine model of the human CNS autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). We employed an experimental platform utilizing single-cell transcriptomic and epigenomic profiling of bone marrow-chimeric mice to categorically distinguish BMC from microglia during CNS autoimmunity. Analysis of gene expression and chromosomal accessibility identified CD88(+)CD317(+) myeloid cells in the CNS of EAE mice as originating from BMC and microglia. Interestingly, each cell lineage exhibited overlapping and unique gene expression patterns and transcription factor motifs that allowed their segregation. Our observations will facilitate determining pathogenic contributions of BMC and microglia in CNS autoimmune disease. Ultimately, this agnostic characterization of myeloid cells will be required for devising disease stage-specific and tissue-specific interventions for CNS inflammatory and neurodegenerative disorders.