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1.
Nat Immunol ; 19(5): 1-7, 2018 05.
Article in English | MEDLINE | ID: mdl-29662171

ABSTRACT

The cytokine transforming growth factor-ß (TGF-ß) regulates the development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF-ß is not critical for microglia survival but is required for the maintenance of the microglia-specific homeostatic gene signature1,2. Under defined host conditions, circulating monocytes can compete for the microglial niche and give rise to long-lived monocyte-derived macrophages residing in the central nervous system (CNS)3-5. Whether monocytes require TGF-ß for colonization of the microglial niche and maintenance of CNS integrity is unknown. We found that abrogation of TGF-ß signaling in CX3CR1+ monocyte-derived macrophages led to rapid onset of a progressive and fatal demyelinating motor disease characterized by myelin-laden giant macrophages throughout the spinal cord. Tgfbr2-deficient macrophages were characterized by high expression of genes encoding proteins involved in antigen presentation, inflammation and phagocytosis. TGF-ß is thus crucial for the functional integration of monocytes into the CNS microenvironment.


Subject(s)
Brain/immunology , Demyelinating Diseases/immunology , Macrophages/pathology , Spinal Cord/immunology , Transforming Growth Factor beta/immunology , Animals , Brain/metabolism , Brain/pathology , Demyelinating Diseases/metabolism , Demyelinating Diseases/pathology , Macrophages/immunology , Macrophages/metabolism , Mice , Signal Transduction , Spinal Cord/metabolism , Spinal Cord/pathology , Transforming Growth Factor beta/metabolism
2.
Glia ; 68(7): 1466-1478, 2020 07.
Article in English | MEDLINE | ID: mdl-32039516

ABSTRACT

Microglia are implicated in the pathophysiology of several neurodegenerative disorders, including Alzheimer's disease. While the role of microglia and peripheral macrophages in regulating amyloid beta pathology has been well characterized, the impact of these distinct cell subsets on tau pathology remains poorly understood. We and others have recently demonstrated that monocytes can engraft the brain and give rise to long-lived parenchymal macrophages, even under nonpathological conditions. We undertook the current study to investigate the regulation of tau pathology by microglia and peripheral macrophages using hTau transgenic mice, which do not exhibit microglial activation/pathology or macrophage engraftment. To assess the direct impact of microglia on tau pathology we developed a protocol for long-term microglial depletion in Cx3cr1CreER R26DTA mice and crossed them with hTau mice. We then depleted microglia up to 3 months in both young and old mice, but no net change in forebrain soluble oligomeric tau or total or phosphorylated levels of aggregated tau was recorded. To investigate the consequence of peripherally-derived parenchymal macrophages on tau aggregation we partially repopulated the hTau microglial pool with peripheral macrophages, but this also did not affect levels of tau oligomers or insoluble aggregates. Our study questions the direct involvement of microglia or peripheral macrophages in the development of tau pathology in the hTau model.


Subject(s)
Alzheimer Disease/pathology , Macrophages/metabolism , Microglia/metabolism , Tauopathies/pathology , tau Proteins/metabolism , Alzheimer Disease/metabolism , Animals , Brain/pathology , Disease Models, Animal , Mice, Transgenic , Microglia/pathology , Monocytes/metabolism
3.
Nanomedicine ; 14(8): 2575-2586, 2018 11.
Article in English | MEDLINE | ID: mdl-30179669

ABSTRACT

We investigated the biotransformation of very small superparamagnetic iron oxide nanoparticles (VSOP) in atherosclerotic LDLR-/- mice. Transmission electron microscopy revealed an uptake of VSOP not only by macrophages but also by endothelial cells in liver, spleen, and atherosclerotic lesions and their accumulation in the lysosomal compartment. Using magnetic particle spectroscopy (MPS), we show that the majority of VSOP's superparamagnetic iron was degraded within 28 days. MPS spectrum shape indicated changes in the magnetic properties of VSOP during the biodegradation process. Experiments with primary murine bone marrow derived macrophages, primary murine liver sinusoidal endothelial cells, and primary human aortic endothelial cells demonstrated that loading with VSOP induced a differential response of cellular iron homeostasis mechanisms with increased levels of ferritin and iron transport proteins in macrophages and increased levels of ferritin in endothelial cells.


Subject(s)
Atherosclerosis/metabolism , Ferric Compounds/chemistry , Ferric Compounds/metabolism , Magnetite Nanoparticles/administration & dosage , Receptors, LDL/physiology , Animals , Aorta/cytology , Aorta/metabolism , Atherosclerosis/physiopathology , Capillaries/cytology , Capillaries/metabolism , Cell Proliferation , Cells, Cultured , Endothelium, Vascular/cytology , Endothelium, Vascular/metabolism , Ferritins/metabolism , Humans , Macrophages/cytology , Macrophages/metabolism , Magnetite Nanoparticles/chemistry , Male , Mice , Mice, Knockout
4.
Oncogene ; 40(32): 5066-5080, 2021 08.
Article in English | MEDLINE | ID: mdl-34021259

ABSTRACT

Intratumoral heterogeneity is a characteristic of glioblastomas that contain an intermixture of cell populations displaying different glioblastoma subtype gene expression signatures. Proportions of these populations change during tumor evolution, but the occurrence and regulation of glioblastoma subtype transition is not well described. To identify regulators of glioblastoma subtypes we utilized a combination of in vitro experiments and in silico analyses, using experimentally generated as well as publicly available data. Through this combined approach SOX2 was identified to confer a proneural glioblastoma subtype gene expression signature. SFRP2 was subsequently identified as a SOX2-antagonist, able to induce a mesenchymal glioblastoma subtype signature. A subset of patient glioblastoma samples with high SFRP2 and low SOX2 expression was particularly enriched with mesenchymal subtype samples. Phenotypically, SFRP2 decreased tumor sphere formation, stemness as assessed by limiting dilution assay, and overall cell proliferation but increased cell motility, whereas SOX2 induced the opposite effects. Furthermore, an SFRP2/non-canonical-WNT/KLF4/PDGFR/phospho-AKT/SOX2 signaling axis was found to be involved in the mesenchymal transition. Analysis of human tumor tissue spatial gene expression patterns showed distinct expression of SFRP2- and SOX2-correlated genes in vascular and cellular areas, respectively. Finally, conditioned media from SFRP2 overexpressing cells increased CD206 on macrophages. Together, these findings present SFRP2 as a SOX2-antagonist with the capacity to induce a mesenchymal subtype transition in glioma cells located in vascular tumor areas, highlighting its role in glioblastoma tumor evolution and intratumoral heterogeneity.


Subject(s)
Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Glioblastoma/etiology , Glioblastoma/metabolism , Membrane Proteins/genetics , SOXB1 Transcription Factors/genetics , Carrier Proteins , Cell Line, Tumor , Gene Expression Profiling , Glioblastoma/pathology , Humans , Kruppel-Like Factor 4/metabolism , Macrophages/immunology , Macrophages/metabolism , Macrophages/pathology , Membrane Proteins/metabolism , Organ Specificity , Protein Binding , Proto-Oncogene Proteins c-akt/metabolism , Receptors, Platelet-Derived Growth Factor/metabolism , SOXB1 Transcription Factors/metabolism , Signal Transduction
5.
Nat Commun ; 9(1): 4845, 2018 11 19.
Article in English | MEDLINE | ID: mdl-30451869

ABSTRACT

Circulating monocytes can compete for virtually any tissue macrophage niche and become long-lived replacements that are phenotypically indistinguishable from their embryonic counterparts. As the factors regulating this process are incompletely understood, we studied niche competition in the brain by depleting microglia with >95% efficiency using Cx3cr1CreER/+R26DTA/+ mice and monitored long-term repopulation. Here we show that the microglial niche is repopulated within weeks by a combination of local proliferation of CX3CR1+F4/80lowClec12a- microglia and infiltration of CX3CR1+F4/80hiClec12a+ macrophages that arise directly from Ly6Chi monocytes. This colonization is independent of blood brain barrier breakdown, paralleled by vascular activation, and regulated by type I interferon. Ly6Chi monocytes upregulate microglia gene expression and adopt microglia DNA methylation signatures, but retain a distinct gene signature from proliferating microglia, displaying altered surface marker expression, phagocytic capacity and cytokine production. Our results demonstrate that monocytes are imprinted by the CNS microenvironment but remain transcriptionally, epigenetically and functionally distinct.


Subject(s)
Brain/immunology , Cell Lineage/immunology , Gene Expression Regulation/immunology , Microglia/immunology , Monocytes/immunology , Adoptive Transfer , Animals , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antigens, Ly/genetics , Antigens, Ly/immunology , Bacterial Proteins/immunology , Bone Marrow Cells/cytology , Bone Marrow Cells/immunology , Brain/cytology , Brain/radiation effects , CX3C Chemokine Receptor 1/genetics , CX3C Chemokine Receptor 1/immunology , Cell Lineage/radiation effects , Cell Proliferation , DNA Methylation , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/immunology , Interferon Type I/genetics , Interferon Type I/immunology , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Luminescent Proteins/immunology , Macrophages/cytology , Macrophages/immunology , Macrophages/radiation effects , Mice , Mice, Transgenic , Microglia/cytology , Microglia/radiation effects , Monocytes/cytology , Monocytes/radiation effects , Monocytes/transplantation , Phagocytosis , Receptors, Mitogen/genetics , Receptors, Mitogen/immunology , Signal Transduction , Transplantation Chimera , Whole-Body Irradiation
6.
Front Aging Neurosci ; 9: 234, 2017.
Article in English | MEDLINE | ID: mdl-28804456

ABSTRACT

While bone marrow-derived Ly6Chi monocytes can infiltrate the central nervous system (CNS) they are developmentally and functionally distinct from resident microglia. Our understanding of the relative importance of these two populations in the distinct processes of pathogenesis and resolution of inflammation during neurodegenerative disorders was limited by a lack of tools to specifically manipulate each cell type. During recent years, the development of experimental cell-specific depletion models has enabled this issue to be addressed. Herein we compare and contrast the different depletion approaches that have been used, focusing on the respective functionalities of microglia and monocyte-derived macrophages in a range of neurodegenerative disease states, and discuss their prospects for immunotherapy.

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