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RNA sequencing of monocytes and microglia from mice with experimental autoimmune encephalomyelitis illustrates a changing phenotype with disease course

ABSTRACT: The role of microglia and infiltrating monocytes in experimental autoimmune encephalomyelitis (EAE) pathogenesis has been controversial. To gain insight into their respective roles, we developed a method for differentiating between microglia and infiltrating monocytes in the CNS using CD44. We used this system to monitor changes in cell number, activation status, and gene expression by RNA sequencing (RNA-Seq) over the course of disease. This in vivo characterization and RNA-Seq dataset improves our understanding of myeloid cell biology in the brain under inflammatory conditions and may lead to strategies to identify therapies for inflammatory pathways active in neuroinflammatory diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE59725 | GEO | 2014/10/20

SECONDARY ACCESSION(S): PRJNA256045

REPOSITORIES: GEO

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Project description:Compelling evidence has shown that interferon (IFN)-γ has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-γ may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-γ at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-γ administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b+ myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from spinal cord of IFN-γ-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-γ and neuroantigen promoted a significantly higher induction of CD4+ regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-β secretion. Additionally, IFN-γ-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-γ-treated EAE mice had a significantly higher frequency of CX3CR1high MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1highPD-L1lowCD11b+Ly6G- cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1highPD-L1low MG). Amelioration of clinical symptoms and induction of CX3CR1highPD-L1low MG by IFN-γ were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-γ promoted the induction of homeostatic CX3CR1highPD-L1low MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-γ plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-γ in EAE.

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RNA sequencing of monocytes and microglia from mice with experimental autoimmune encephalomyelitis illustrates a changing phenotype with disease course

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