Multiple sclerosis (MS) is characterized by pathological inflammation that results from the recruitment of lymphoid and myeloid immune cells from the blood into the brain. Due to subset heterogeneity, defining the functional roles of the various cell subsets in acute and chronic stages of MS has been challenging. Here, we used index and transcriptional single-cell sorting to characterize the mononuclear phagocytes that infiltrate the central nervous system from the periphery in mice with experimentally induced autoimmune encephalomyelitis, a model of MS. We identified eight monocyte and three dendritic cell subsets at acute and chronic disease stages in which the defined transcriptional programs pointed toward distinct functions. Monocyte-specific cell ablation identified Cxcl10+ and Saa3+ monocytic subsets with a pathogenic potential. Transfer experiments with different monocyte and precursor subsets indicated that these Cxcl10+ and Saa3+ pathogenic cells were not derived from Ly6C+ monocytes but from early myeloid cell progenitors. These results suggest that blocking specific pathogenic monocytic subsets, including Cxcl10+ and Saa3+ monocytes, could be used for targeted therapeutic interventions.
Bibliographical noteFunding Information:
We thank V. Malchin for excellent technical assistance, J. Priller for support, the MDC animal facility (especially J. Bergemann) and the MDC and WIS FACS facilities (especially H.-P. Rahn). A.M. is a Heisenberg fellow supported by the DFG (MI1328). I.A. is supported by the Chan-Zuckerberg Initiative, the HHMI International Scholar award, the European Research Council Consolidator grant (724471-HemTree2.0), the Thompson Family Foundation, an MRA Established Investigator Award (509044), the Israel Science Foundation (703/15), the Ernest and Bonnie Beutler Research Program for Excellence in Genomic Medicine, the Helen and Martin Kimmel award for innovative investigation, an International Progressive MS Alliance/NMSS PA-1604-08459 and an Adelis Foundation grant. S.J. is supported by the International Progressive MS Alliance/ NMSS PA-1604-08459.
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