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A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. [bulk RNA-Seq]

ABSTRACT: While the roles of parenchymal microglia in brain homeostasis and disease are fairly clear, other brain-resident myeloid cells remain less understood. By dissecting border regions and combining single-cell RNA sequencing with high-dimensional cytometry, bulk RNA-sequencing, fate-mapping and microscopy, we reveal the diversity of non-parenchymal brain macrophages. Border-associated macrophages (BAMs) residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets with tissue-specific transcriptional signatures, and their cellular composition changed during postnatal development. BAMs exhibited a mixed ontogeny and subsets displayed distinct self-renewal capacities upon depletion and repopulation. Single-cell and fate-mapping analysis both suggested there is a unique microglial subset residing on the apical surface of the choroid plexus epithelium. Finally, gene network analysis and conditional deletion revealed IRF8 as a master regulator that drives the maturation and diversity of brain macrophages. Our results provide a framework for understanding host-macrophage interactions in the healthy and diseased brain.

ORGANISM(S): Mus musculus

PROVIDER: GSE128781 | GEO | 2019/03/27

REPOSITORIES: GEO

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A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. [scRNA-Seq]

Project description:While the roles of parenchymal microglia in brain homeostasis and disease are fairly clear, other brain-resident myeloid cells remain less understood. By dissecting border regions and combining single-cell RNA sequencing with high-dimensional cytometry, bulk RNA-sequencing, fate-mapping and microscopy, we reveal the diversity of non-parenchymal brain macrophages. Border-associated macrophages (BAMs) residing in the dura mater, subdural meninges and choroid plexus consisted of distinct subsets with tissue-specific transcriptional signatures, and their cellular composition changed during postnatal development. BAMs exhibited a mixed ontogeny and subsets displayed distinct self-renewal capacities upon depletion and repopulation. Single-cell and fate-mapping analysis both suggested there is a unique microglial subset residing on the apical surface of the choroid plexus epithelium. Finally, gene network analysis and conditional deletion revealed IRF8 as a master regulator that drives the maturation and diversity of brain macrophages. Our results provide a framework for understanding host-macrophage interactions in the healthy and diseased brain.

2019-03-27 | GSE128854 | GEO

Early fate defines microglia and non-parenchymal brain macrophage development

Project description:Central nervous system (CNS) macrophages comprise parenchymal microglia and border-associated macrophages (BAMs) residing in the meninges, the choroid plexus and the perivascular spaces. With the exception of choroid plexus macrophages, most CNS macrophages emerge during primitive hematopoiesis in the extra-embryonic yolk sac. What remains unknown however, is whether microglia and BAMs share a developmental program or arise from separate predefined lineages. Here, we identified two phenotypically, transcriptionally and locally distinct brain macrophage populations throughout development, giving rise to microglia and BAMs. Two independent macrophage populations were already present in the yolk sac prior to their seeding of the brain. Using fate-mapping system, we demonstrate that in contrast to microglia, the pool of embryonic BAMs in the choroid plexus and the meninges was gradually replaced by precursors emerging later in embryogenesis. The development of microglia was dependent on TGF-β whereas the genesis and maturation of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages are separate entities in terms of ontogeny, gene expression signatures and requirement for TGF-β.

2020-04-16 | GSE146928 | GEO

Early fate defines microglia and non-parenchymal brain macrophage development

2020-04-15 | GSE146926 | GEO

Perivascular macrophages proliferate in the CNS, but also contributed by bone-marrow precursors in response to cerebral ischemia

Project description:Immune response following CNS disease and injury comprises three different compartments, parenchymal, perivascular and blood involving specialized immune cells. Microglia are the major immune cell residing in the CNS parenchymal compartment but together with other macrophages which are residing in the non-parenchymal structures such as perivascular spaces, leptomeninges and choroid plexus constitute the total macrophage population of the CNS. While the homeostatic functions of these specialized macrophages in not very well understood, evidence shows that these macrophages at the blood-brain interface might involve immune-surveillance and establish a gate way for the recruitment of peripheral immune cells in to the CNS in response to the pathological stimuli. In humans and rats these macrophages identified exclusively by the high levels of scavenger receptor CD163

2019-06-30 | GSE99206 | GEO

Fetal toll-like receptor 3 signalling contributes to the induction of autism-like behaviors in a mouse model of maternal immune activation

Project description:A mouse model of maternal immune activation (MIA) is commonly used to study neurodevelopmental disorders. Gene expression analysis has suggested that fetal brain macrophages may be activated by MIA, but it is unclear whether these transcriptional changes connect to behavioral phenotypes in offspring. Here, we have shown that the induction of autism spectrum disorder (ASD)-like behavioral phenotypes by MIA in male offspring is dependent upon fetal activation of the toll-like receptor 3 (TLR3) signaling molecule TRIF. Using single-cell RNA sequencing, we identified a cluster of border-associated macrophages (BAMs) that was significantly enriched in wild-type fetal brains following TLR3-MIA but not diminished in Trif -/- fetal brains. Moreover, after TLR3-MIA, the number of fetal BAMs in the choroid plexus, but not in the meninges, was increased, and these cells were characterized by increased S100a8/9 expression. Finally, we proposed that activation of fetal TLR3-TRIF signaling was induced by transplacental viral infection. Overall, our data suggest that fetal TLR3 signaling contributes to MIA-induced ASD-like behavioral phenotypes in mice.

2022-02-08 | GSE196151 | GEO

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

Project description:The immune cells of the central nervous system (CNS) comprise parenchymal microglia and at the CNS border regions meningeal, perivascular and choroid plexus macrophages (summarized as CNS-associated macrophages, CAMs). Previous work has uncovered that microglial properties are strongly dependent on environmental signals from the commensal microbiota while its effect on CAMs remained unknown. By combining several microbiota manipulation approaches, genetic mouse models and single-cell RNA-sequencing, we comprehensively characterized CNS myeloid cell composition and function. Under steady-state, the transcriptional profile and numbers of choroid plexus macrophages were found to be tightly steered by complex microbiota. Divergently, perivascular and meningeal macrophages were affected to a lesser extent. An acute perturbation through viral infection evoked an attenuated immune response of all CAMs in germ-free mice. Additionally, we assessed CAMs in a more chronic pathological state in 5xFAD mice as a model for Alzheimer’s disease whereby exclusively perivascular macrophages displayed enhanced amyloid beta uptake in GF 5xFAD mice. Our results provide novel insights for understanding distinct microbiota-CNS macrophage interactions during health and perturbation that could potentially be targeted therapeutically.

2021-10-01 | GSE178956 | GEO

Gene expression profiles obtained from laser-microdissected human choroid plexus papilloma cells

Project description:Gene expression profiles generated from human tumor cells laser-microdissected from surgical samples of seven choroid plexus papillomas (Grade I WHO) as eight samples of epithelial cells lasermicrodissected from normal choroid plexus obtained at autopsy. Choroid plexus tumors are rare pediatric brain tumors derrived from the choroid plexus epithelium. Gene expression profiles of lasermicrodissected tumor cells from 7 individual choroid plexus tumor samples obtained at surgery were compared to gene expression profiles from non-neoplastic choroid plexus epithelial cells lasermicrodissected from normal non-neoplastic choroid plexus obtained at autopsy (Am J Surg Pathol. 2006 Jan;30(1):66-74.) in order to identfy genes differentially expressed in choroid plexus tumor cells.

2009-02-01 | E-GEOD-14098 | biostudies-arrayexpress

Differential plasticity and fate of brain-resident and recruited macrophages during the onset and resolution of neuroinflammation

Project description:Microglia and border-associated macrophages (BAMs) are brain-resident self-renewing cells with important homeostatic functions. However, their fate during and after severe episodes of brain inflammation and their relation to recruited monocyte-derived cells remain poorly understood. Here, we show that Trypanosoma brucei parasites invade the brain via its border regions, triggering a disruption of brain barriers and the recruitment of large numbers of monocytes. Fate-mapping combined with single-cell sequencing revealed the remarkable dynamics of resident macrophages, including microglia accumulation around the ventricular ependyma and an expansion of epiplexus cells. Resident macrophages were important for attracting peripheral immune cells and driving a pro-inflammatory response. However, recruited monocyte-derived macrophages reached higher cell densities and exhibited more transcriptional plasticity, adopting anti-microbial gene expression profiles not observed resident macrophages. Remarkably, recruited macrophages were short-lived and rapidly removed upon disease resolution, while activated resident macrophages progressively reverted towards a homeostatic state. Long-term transcriptional alterations were limited for microglia but more pronounced in BAMs. Together our results reveal the diverging responses and dynamics of resident and recruited macrophages upon Trypanosome invasion of the brain.

2022-08-26 | GSE212078 | GEO

OTX2 homeoprotein regulates adult choroid plexus activity

Project description:Choroid plexus secretes cerebrospinal fluid important for brain development and homeostasis. The OTX2 homeoprotein is critical for choroid plexus development and remains highly expressed in adult choroid plexus. Through RNA sequencing analyses of constitutive and conditional knockdown adult mouse models, we reveal putative roles for OTX2 in choroid plexus function, including cell signaling and adhesion, and show that it regulates the expression of factors secreted into cerebrospinal fluid, notably transthyretin. We also show that Otx2 expression impacts choroid plexus immune and stress responses, and also affects splicing which leads to changes in mRNA isoforms of proteins implicated in oxidative stress response and DNA repair. Through mass spectrometry analysis of OTX2 protein partners in the choroid plexus, and in known non-cell autonomous target regions such as visual cortex and subventricular zone, we identified putative targets involved in cell adhesion, chromatin structure and RNA processing. Thus, OTX2 retains important roles in choroid plexus function and brain homeostasis throughout life.

2021-08-31 | GSE157386 | GEO

Choroid Plexus-Derived Insulin Inhibits Feeding via Direct Signaling through Arcuate Nucleus

Project description:The choroid plexus is an important source of trophic factors for the developing and mature brain. Recently we described the expression and production of mature insulin in epithelial cells of the choroid plexus, and how its secretion can be modulated by serotonin through Htr2c, a metabotropic receptor that signals via Gq. To understand the function of this choroid plexus-derived insulin, here we describe a way to genetically target epithelial cells of the choroid plexus using a viral vector. With this, we modulated insulin expression and evaluated behavior. Insulin overexpression in the choroid plexus of wild type mice led to an inhibition in feeding, whereas insulin knockdown in choroid plexus of Ins1-/-Ins2fl/fl mice promoted discrete increases in food intake, especially after a period of fasting. Insulin overexpression in choroid plexus induced roust transcriptomic changes in the hypothalamus, most of which related to axonal growth and synapse-related processes. Finally, activation of Gq signaling in insulin-overexpressing choroid plexuses led to acute AKT phosphorylation in neurons of the arcuate nucleus, suggesting a direct action, through the CSF, of choroid plexus-derived insulin on the hypothalamus. Taken together our findings prove that the choroid plexus is a relevant source of insulin in the central nervous system, with physiological implications in feeding behavior. We believe that choroid plexus-derived insulin has to be taken into consideration in future work pertaining insulin actions in the brain.

2022-12-15 | GSE218188 | GEO

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