RNA sequencing from the microglia of mice with acute GvHD against syngeneic bone marrow transplanted and untreated controls
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE141663 | GEO | 2020/01/13
REPOSITORIES: GEO
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Project description:RNA sequencing from the microglia of mice with acute GvHD against syngeneic bone marrow transplanted and untreated controls
| PRJNA594334 | ENA
Project description:Graft-versus-host disease (GVHD) remains the leading cause of non-relapse mortality after allogeneic stem cell transplantation for haematological malignancies. Manifestations of GVHD in the central nervous system (CNS) present as neurocognitive dysfunction in up to 60% of patients, however, the mechanisms driving chronic GVHD in the CNS are yet to be elucidated. Our studies of murine chronic GVHD revealed a spatial learning and memory deficit associated with inflammation in the hippocampus underlain by persistent Ifng upregulation. By flow cytometry, we observed a proportional shift in the donor-derived T-cell population in the chronic GVHD brain from early CD8 dominance to later CD4 sequestration. Hippocampal RNA sequencing identified perturbations to structural and functional synapse-related gene expression, together with the upregulation of genes associated with IFN-γ responses and antigen presentation. Neuroinflammation in the cortex of mice and humans during acute GVHD was recently shown to be mediated by resident microglia-derived TNF. In contrast, infiltration of pro-inflammatory MHC class II+ donor bone marrow-derived macrophages (BMDM) was identified as a distinguishing feature of CNS chronic GVHD. Donor BMDM, which comprised up to 50% of the CNS myeloid population, exhibited a transcriptional signature distinct from resident microglia. Recipients of MHC class II knockout bone marrow grafts exhibited attenuated neuroinflammation, suggestive of a critical role for donor BMDM in chronic CNS GVHD. Our identification of disease mediators distinct from those in the acute phase indicates the necessity to pursue alternative therapeutic targets for late-stage neurological manifestations.
2021-08-18 | GSE179441 | GEO
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.
2016-10-19 | E-MTAB-5077 | biostudies-arrayexpress
Project description:Gene profiling of CNS-derived microglia vs splenic CD11b+Ly6C+ monocyte subsets deom adult mice Gene array identified 1572 genes that were enriched in microglia vs. 611 monocyte enriched genes with a greater than 5-fold difference (P<0.001). Gene profiling of CD11b+CD45Low microglia isolated from the CNS and CD11b+Ly6C+ monocyte subsets isolated from the spleen of naM-CM-/ve adult mice.
2013-07-08 | E-GEOD-48579 | biostudies-arrayexpress
Project description:Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called ‘microgliopathies’. However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulated the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signalling. Unexpectedly, the Usp18-mediated feedback loop was independent from the catalytic domain of the protease but instead required the interacting region of Ifnar2. Additionally, the absence of Ifnar1 completely rescued microglial activation indicating a tonic IFN signal mediated by receptor interactions under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal and myelin damage and determined the spatial distributions of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as novel negative regulator of microglia activation, demonstrate a protective role of the IFNAR pathway for microglia and establish Usp18 as potential therapeutic target for the treatment of MS. Primary microglia (WT, USP18ko and USP18_C61A mice) and BV-2 cells (treated with control siRNA or siRNA against USP18) were incubated with 500 U/ml IFN-b. At different timepoints (0h, 6h, and 24h) RNA samples were taken and analyzed via Microarray
2015-04-20 | E-GEOD-61500 | biostudies-arrayexpress
Project description:Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is an inherited brain and bone disease. It manifests as dementia and bone fractures. The PLOSL phenotype is caused by loss-of-function mutations in one of the two genes encoding the components of the DAP12/TREM2 receptor complex. The DAP12/TREM2 complex is expressed in cells of the myeloid lineage, including microglia in the central nervous system (CNS). The molecular mechanisms producing the CNS phenotype of PLOSL remain largely unknown. To gain insight into dysfunctional CNS pathways behind PLOSL, we performed genome-wide expression analysis of Dap12 (Tyrobp)-deficient mouse microglial cells. Keywords: knock-out response Transcript profiles of three wild type and three Dap12-deficient primary microglial cultures were analyzed.
2011-08-23 | E-GEOD-9043 | biostudies-arrayexpress
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
2015-07-15 | E-GEOD-68376 | biostudies-arrayexpress
Project description:As tissue macrophages of the central nervous system (CNS), microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. Here we reveal significant contributions of the host microbiota to microglia homeostasis as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulate microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings reveal that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be restored to some extent by complex microbiota. For acute inflammatory challenges, LPS was applied intracranially and 6 hours later, animals were analyzed. Control animals were injected PBS i.c. Transcriptional profiles of FACS-sorted microglia were assessed using Affymetrix® (Santa Clara, USA) GeneChip Arrays (Mouse Gene 2.1 ST Arrays).
2015-05-25 | E-GEOD-62201 | biostudies-arrayexpress
Project description:Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene expression and phenotypic profile of a variety of endogenous CNS cell types (astrocytes, neurons, microglia) as well as an influx of leukocytic cells (neutrophils, macrophages, T-cells) from the periphery. Many molecules and conditions can trigger a transformation of ârestingâ (or surveying) microglia to an âactivatedâ (alerted/reactive) state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. Emphasis is placed on the role of specific molecular signaling systems such as hypoxia inducible factor-1 (HIF-1) and toll-like receptor-4 (TLR4) in regulating the microglial response in this setting. We then review histological and recent novel radiological data that confirms a key role for microglial activation in the setting of ischemic stroke in humans. We discuss recent progress in the pharmacological and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in preemptively targeting microglial activation in order to reduce stroke severity. 12 arrays, 4 experimental groups, 3 replicates in each group, CN is control normoxia, CH is control hypoxia, TN is TLR4 knockout normoxia, TH is TLR4 knockout hypoxia.
2010-10-05 | E-GEOD-18602 | biostudies-arrayexpress
Project description:Infiltrating monocyte derived macrophages (MDMs) and resident microglia dominate CNS injury sites. We show that MDMs and microglia can directly communicate to modulate each other’s function. Also, the presence of MDMs in CNS injury suppresses microglia-mediated phagocytosis and inflammation. We suggest that macrophages infiltrating the injured CNS provide a mechanism to control acute and chronic microglia-mediated inflammation, which could otherwise drive damage in a variety of CNS conditions. To understand the global effects of macrophage communication to microglia, we transcriptionally profiled activated adult mouse microglia in the presence or absence of macrophages with and without an inflammatory stiumulus (LPS)
2018-08-01 | GSE102482 | GEO