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Multiomic spatial landscape of innate immune cells at human central nervous system borders

ABSTRACT: The innate immune system of the human central nervous system (CNS) is highly diverse already during homeostasis. Several immune cell populations such as macrophages that are frequent in the brain parenchyma (microglia) and less numerous at the brain interfaces as CNS-associated macrophages (CAMs) constitute the local immune compartment. Due to their scantiness and particular location, little is known about the presence of temporally and spatially restricted CAM subclasses during development, health and perturbation. Here, we combined several high-dimensional technologies, such as single-cell RNA-sequencing, time-of-flight mass cytometry and single-cell spatial transcriptomics with fate mapping and advanced immunohistochemistry to comprehensively characterize the immune system at human CNS interfaces. We also provide a comprehensive analysis of resident and engrafted myeloid cells in the brains of individuals with peripheral blood stem cell transplantation, revealing remarkable dynamics. These approaches enabled us to identify a previously unappreciated spectrum of transcriptional classes of human CAMs and to decipher their turnover with circulating cells. CAM signatures profoundly changed during ontogeny and pathology. Our results highlight myeloid diversity at the interfaces of the human CNS with the periphery and provide new insights into the human brain’s immune system.

ORGANISM(S): Homo sapiens

PROVIDER: GSE245311 | GEO | 2023/12/20

REPOSITORIES: GEO

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HOST MICROBIOTA REGULATE SELECTIVE MYELOID SUBSETS IN THE CENTRAL NERVOUS SYSTEM DURING HOMEOSTASIS AND DISEASE

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2021-10-01 | GSE178956 | GEO

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2022-01-27 | GSE194433 | GEO

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Project description:Objective: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by a global increasing incidence driven by relapsing-remitting disease in females. p38 MAP kinase (MAPK) has been described as a key regulator of inflammatory responses in autoimmunity, but its role in the sexual dimorphism in MS or MS models remains unexplored. Methods: Toward this end, we used experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS, combined with pharmacologic and genetic inhibition of p38 MAPK activity and transcriptomic analyses. Results: Pharmacologic inhibition of p38 MAPK selectively ameliorated EAE in female mice. Conditional deletion studies demonstrated that p38M-NM-1 signaling in macrophages/myeloid cells, but not T cells or dendritic cells, recapitulated this sexual dimorphism. Analysis of CNS inflammatory infiltrates showed that female, but not male mice lacking p38M-NM-1 in myeloid cells exhibited reduced immune cell activation compared with controls, while peripheral T cell priming was unaffected in both sexes. Transcriptomic analyses of myeloid cells revealed differences in p38M-NM-1-controlled transcripts comprising female- and male-specific gene modules, with greater p38M-NM-1 dependence of pro-inflammatory gene expression in females. Interpretation: Our findings demonstrate a key role for p38M-NM-1 in myeloid cells in CNS autoimmunity and uncover important molecular mechanisms underlying sex differences in disease pathogenesis. Taken together, our results suggest that the p38 MAPK signaling pathway represents a novel target for much needed disease modifying therapies for MS WT vs. p38alphaCKO macrophages, male vs. female

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