Gene expression of microglia from naïve or MHV infected mouse brains
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE103380 | GEO | 2018/02/28
REPOSITORIES: GEO
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Project description:Several viruses can infect the mammalian nervous system and induce neurological dysfunction. Adoptive immunotherapy (AI) is an approach that involves administration of antiviral T cells and has shown promise in clinical studies for the treatment of peripheral virus infections in humans such as cytomegalovirus, Epstein-Barr virus, and adenovirus, among others. Clearance of neurotropic infections, on the other hand, is particularly challenging because the central nervous system (CNS) is relatively intolerant of immunopathological reactions. Therefore, it is essential to develop and mechanistically understand therapies that noncytopathically eradicate pathogens from the CNS. Here, we used mice persistently infected from birth with lymphocytic choriomeningitis virus (LCMV) to demonstrate that therapeutic antiviral T cells can completely purge the persistently infected brain without causing blood brain barrier breakdown or tissue damage. Mechanistically, this is accomplished through a tailored release of chemoattractants that recruit antiviral T cells, but few pathogenic innate immune cells such as neutrophils and inflammatory monocytes. Upon arrival, T cells enlisted the support of nearly all brain resident myeloid cells (microglia) by converting them into CD11c+ antigen-presenting cells (APCs) – a cell population also found in the brain of a human immunodeficiency virus infected patient. Two-photon imaging studies revealed that antiviral CD8+ and CD4+ T cells interacted directly with CD11c+ microglia and induced STAT1 signaling, but did not initiate programmed cell death. We propose that noncytopathic CNS viral clearance can be achieved by therapeutic antiviral T cells reliant on restricted chemoattractant production and interactions with apoptosis-resistant microglia. 6 Mouse Microglia-sorted Brain Samples: 3 (-) AI, 3 (+) AI.
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Gene expression of macrophages and microglia from naïve or MHV infected mouse brains
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Project description:During early embryogenesis microglia arise from yolk sac progenitors populating the developing CNS, where they are maintained as tissue-resident macrophages throughout the organism’s lifespan. Here, we describe an experimental system that allows the specific conditional ablation of microglia in vivo. Strikingly, we found that the microglia compartment was reconstituted within one week following depletion. Microglia repopulation relied entirely on a CNS-resident, internal pool and was independent from bone marrow-derived precursors. Newly formed microglia were found in highly proliferative, organized micro-clusters that dissolve once steady state was achieved. Gene expression profiling revealed prominent expression of Interleukin-1 (IL-1) receptor in proliferating microglia. During the repopulation phase, IL-1 signaling was neutralized by treatment with IL-1 receptor antagonist that impaired microglia proliferation. Hence, microglia harbor a highly efficient potential to restore themselves without contribution of peripheral myeloid cells. IL-1 signaling significantly participates in this restorative proliferation process and is involved in stabilizing microglia maintenance. bone marrow macrophages, wild type microglia, and repopulating microglia
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Project description:Microglia are the resident macrophages of the central nervous system (CNS). Gene profiling identified the transcriptional regulator Sall1 as a microglia signature gene. Given the high expression of Sall1 in microglia, we sought to identify its function in vivo. The Sall1CreER allele has been targeted into the Sall1 locus, therefore Sall1CreER/fl mice (heterozygous for both alleles) allow inducible ablation of Sall1 expression in microglia after tamoxifen treatment. We performed RNA-seq to examine gene expression profiles of microglia sorted from tamoxifen treated adult Sall1CreER/fl mice and Sall1fl/fl control littermates. Microglia were obtained with > 98% purity and the absence of Sall1 was confirmed in Sall1CreER/fl microglia. We could show that deletion of Sall1 in microglia in vivo resulted in the conversion of these cells from resting tissue macrophages into inflammatory phagocytes leading to altered neurogenesis and disturbed tissue homeostasis. Similar changes in gene expression profiles were found in Sall1-deficient microglia isolated from tamoxifen-treated Cx3cr1CreERSall1fl/fl mice. In these mice, deletion of Sall1 is targeted to CX3CR1+ myeloid cells including microglia and CNS-associated macrophages but not to any other CNS-resident cells. This indicated that Sall1 transcriptional regulation maintains microglia identity and physiological properties in the CNS.
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