The DOI matches its Crossref record; 68 of the 68 references it cites were found in a registry or an index.
A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment
Open accessAbstract
While the roles of parenchymal microglia in brain homeostasis and disease are fairly clear, other brain-resident myeloid cells remain less well 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 capacity following depletion and repopulation. Single-cell and fate-mapping analysis both suggested that 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 both the healthy and diseased brain.
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“Our consensus exAM signature does overlap with the dissociation signature in the study by Van Hove et al.[43] (19 of 25 genes in consensus exAM list; Supplementary Tables 4, 5 and 21a).”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as Van Hove et al.[43]
In the citing paper
“Consistent with the reports from other tissues in mice, we found that typical enzymatic digestion of mouse brain tissue induced a host of transcriptional alterations34,43,44,65.”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as [43]
In the citing paper
“However, emerging results from other tissues/cell types have begun to characterize dissociation artifacts following enzymatic digestion43–45,65,66.”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as [43]
In the citing paper
“No explicit statistical methods were used to predetermine sample sizes but our sample sizes exceed those reported in previous publications32,34,43.”
From Dissection of artifactual and confounding glial signatures by single-cell sequencing of mouse and human brain (2022) · cites this paper as [43]
In the citing paper
“This molecule likely also affects BAMs, as reported in the case of PLX3397 [317], placing an important caveat on the interpretation of data where PLX5622 is assumed to be purely microglia-specific.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [317]
In the citing paper
“Although microglia represent a heterogeneous cell population [46], they still share several expression profiles with primitive and adult macrophages, including IBA1.”
From The Cuprizone Model: Dos and Do Nots (2020) · cites this paper as [46]
In the citing paper
“In the Aging Mouse Brain Single Cell Portal, Plcg2 expression is highest in microglia and brain macrophages, with lower levels in endothelial cells and oligodendrocyte precursor cells and minimal to no expression in neurons, astrocytes, and mature oligodendrocytes [30, 72–74].”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [74]
In the citing paper
“In the Brain Immune Atlas aggregate of CD45+ cells from brain and meningeal regions, Plcg2 transcripts are detected in 18% of immune cells across parenchymal microglia and multiple border-associated macrophage (BAM) subsets, with choroid plexus surface and dural BAMs contributing many Plcg2+ cells and a small B-cell cluster displaying the highest per-cell Plcg2 expression in the dataset [74].”
From PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain (2026) · cites this paper as [74]
In the citing paper
“We identified a classical monocyte cluster that highly express Ly6c2, and a non-classical monocyte cluster highly express Itgal, similarly as a published single cell RNA-seq study.88”
From TET2-mutant myeloid cells mitigate Alzheimer’s disease progression via CNS infiltration and enhanced phagocytosis in mice (2025) · cites this paper as [88]
In the citing paper
“In addition, we confirmed previous findings of elevated expression of lipid-related genes in BAMs (31) and observed an increase in LD content within these cells over time and during disease progression.”
From Reducing microglial lipid load enhances β amyloid phagocytosis in an Alzheimer’s disease mouse model (2025) · cites this paper as [31]
In the citing paper
“MHCII+ macrophages are most abundant in the choroid plexus and meninges [37], and we similarly observe widespread uptake of L2-siRNA in this population (Fig. 5F).”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [37]
In the citing paper
“MHCII+ macrophages are most abundant in the choroid plexus and meninges,43 and we similarly observe widespread uptake of L2-siRNA in this population (Fig. 5F).”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [43]
In the citing paper
“The yolk sac-derived precursors of resident macrophages are only in the perivascular compartment [360,361], where they maintain their cellular origin in adulthood [362,363,364].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [364]
In the citing paper
“As immune surveillants, CAMs clear harmful substances through phagocytosis, antigen presentation, and cytokine production [364,368,371,372,373,374,375,376]”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [364]
In the citing paper
“CD38 expression was associated with neuroinflammation with greater amounts of proinflammatory macrophages/microglia in mouse brains160,165.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [165]
In the citing paper
“This contrasts with macrophages in the choroid plexus and dura mater, which do turn over and receive some input from peripheral blood monocytes during adulthood (71-73).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [73]
In the citing paper
“Like microglia, most macrophages residing in the leptomeninges and perivascular spaces are derived from early yolk sac–derived erythromyeloid progenitors, and during steady state, these cells have minimal turnover.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [73]
In the citing paper
“On the basis of high-parameter mass cytometry and single-cell RNA-sequencing studies, the dural macrophages appear to be distinct from those residing in the pia and underlying parenchyma (73, 94).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [73]
In the citing paper
“The macrophages expressed markers of border associated macrophages (BAMs) (e.g., Apoe, Ms4a7, Ms4a6c) recently identified in periluminal regions, meninges, and ChP (Van Hove et al., 2019).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Van Hove et al., 2019
In the citing paper
“Similarly, we found a subset of macrophages expressing markers previously defined as subdural-specific BAMs (e.g., Lyve1, Ednrb, Colec12; Van Hove et al., 2019) that were enriched in embryonic ChP macrophages in our dataset (Figure S5H).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Van Hove et al., 2019
In the citing paper
“However, in contrast to Van Hove et al., our data revealed that this separation was age-dependent and potentially represented a maturation-dependent shift from MHC IIlow to MHC IIhigh (Figure 5I, S5I,J, Table S6).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Van Hove et al., 2019
In the citing paper
“In agreement with recent reports (Van Hove et al., 2019), we found diversity within the BAMs, which segregated into two subsets defined as major histocompatibility complex (MHC) class IIlow and MHC IIhigh.”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Van Hove et al., 2019
In the citing paper
“These maturation dependent changes agree with a recent report of BAMs (Van Hove et al., 2019).”
From A cellular and spatial map of the choroid plexus across brain ventricles and ages (2021) · cites this paper as Van Hove et al., 2019
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Metadata
- Authors
- Van Hove, H., Martens, L., Scheyltjens, I., De Vlaminck, K., Pombo Antunes, A. R., De Prijck, S., Vandamme, N., De Schepper, S., Van Isterdael, G., Scott, C. L., Aerts, J., Berx, G., Boeckxstaens, G. E., Vandenbroucke, R. E., Vereecke, L., Moechars, D., Guilliams, M., Van Ginderachter, J. A., Saeys, Y., & Movahedi, K.
- Affiliations
- Ghent University (BE)
- Vrije Universiteit Brussel (BE)
- Janssen (Belgium) (BE)
- KU Leuven (BE)
- Ghent University Hospital (BE)
- Corresponding author
- Movahedi, Kiavash
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-05-06
- Volume
- 22
- Issue
- 6
- Pages
- 1021-1035
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2943220296
- Cited by
- 1,074
- References
- 68
- Citations by year
- 2026: 160 · 2025: 156 · 2024: 187 · 2023: 152 · 2022: 148 · 2021: 151 · 2020: 90 · 2019: 29
- FWCI
- 46.98
- Type
- journal article
- Language
- en
- Open access
- green
- lirias.kuleuven.be
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Lirias (submittedVersion, other-oa)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- brain macrophages, border-associated macrophages, choroid plexus, dura mater, microglia, IRF8, macrophage ontogeny, postnatal brain development, self-renewal, cerebrospinal fluid
- MeSH terms
- Interferon Regulatory Factor-8, Animals, Brain, Cell Differentiation, Female, Macrophages, Male, Mice, Inbred C57BL, Microglia, Cell Lineage, Interferon Regulatory Factors, Mice
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