Single-Cell Mass Cytometry Reveals Molecular Signatures of Inflammation in Models of Neuroinflammation versus Neurodegeneration Ajami B, Samusik N, Wieghofer P, HoP, CrottiA, BjornsonB, Prinz M, Fantl W, Nolan G, Steinman L. Stanford University School of Medicine, Stanford, CA, USA Two polarities are the subject of much attention in brain pathology: neuroinflammation versus neurodegeneration. Here, we analyzed these polarities in three models of disease with single-cell mass cytometry (CyToF) using unbiased data analysis platform. Comparing myeloid cells in the quintessential model of neuroinflammation experimental autoimmune encephalomyelitis (EAE), versus two neurodegenerative conditions: the R6/2 mouse model of Huntington's disease (HD) and the superoxide dismutase 1 (mSOD1) transgenic model of amyotrophic lateral sclerosis (ALS), we identified three myeloid cell populations exclusive to the central nervous system (CNS), and present in both neuroinflammatory and neurodegenerative conditions. Blood-derived monocytes, the counterpart of CNS-resident myeloid cells, consist of five populations and migrate to the brain in EAE but were absent in HD and ALS. Single-cell analysis revealed a vast disparity in signaling activity and cytokine production within similar myeloid populations in EAE compared to HD and ALS. In EAE, tightly organized signaling events occur in a stepwise manner, whereas these same signaling events are absent in HD. Furthermore, there is a notable difference in the cytokine profile at the single-cell level between these two polarities of neuropathology, where multifunctional cells simultaneously secreting multiple cytokines correlated best with neuroinflammation in EAE. These findings emphasize the differences in neuropathology between inflammatory and degenerative brain disease, and reveal selective therapeutic targets for these specific brain pathologies, such as targeting 5 integrin on myeloid cells to treat neuroinflammation.
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