Identification of a Cxcl10+ monocyte subset with a pathogenic signature in the CNS during auto-immune neuroinflammation

Multiple Sclerosis (MS) is characterized by pathological inflammation resulting from recruitment of lymphoid and myeloid immune cells from the blood circulation into the central nervous system (CNS). Due to cellular heterogeneity, defining the functional roles of these subsets in acute and chronic stages of MS has been challenging. Here we used index sorting and transcriptional single-cell sequencing to characterize peripheral mononuclear phagocyte infiltrates in the MS mouse model, experimental autoimmune encephalomyelitis (EAE). Based on their transcriptomes, we identified eight monocyte and three dendritic cell subsets during disease pathology with defined characteristics pointing towards distinct functions. Cell ablation identified two specific monocytic subsets with a pathogenic potential. Congenic monocyte transfer experiments combined with indexed-lineage sorting coupled to scRNA-seq established that these pathogenic cells are not descendants of the canonical Ly6C+ monocytes but derived from early myeloid cell progenitors. These results suggest a potential for targeted therapeutic interventions aimed at blocking specific pathogenic monocytic subsets. Overall design: Transcriptional profiling of myeloid cells (monocytes, macrophages and dendritic cells) from murine spinal cords, 16 days (acute phase) and 30 days (chronic phase) post induced Experimental Autoimmune Encephalomyelitis (EAE) immunization.