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Macrophages at CNS interfaces: ontogeny and function in health and disease
Abstract
The segregation and limited regenerative capacity of the CNS necessitate a specialized and tightly regulated resident immune system that continuously guards the CNS against invading pathogens and injury. Immunity in the CNS has generally been attributed to neuron-associated microglia in the parenchyma, whose origin and functions have recently been elucidated. However, there are several other specialized macrophage populations at the CNS borders, including dural, leptomeningeal, perivascular and choroid plexus macrophages (collectively known as CNS-associated macrophages (CAMs)), whose origins and roles in health and disease have remained largely uncharted. CAMs are thought to be involved in regulating the fine balance between the proper segregation of the CNS, on the one hand, and the essential exchange between the CNS parenchyma and the periphery, on the other. Recent studies that have been empowered by major technological advances have shed new light on these cells and suggest central roles for CAMs in CNS physiology and in the pathogenesis of diseases.
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“They belong to CNS border-associated macrophages (CAMs) [367,368].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [367]
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“Single-cell profiling suggested functions shared with microglia and astrocytes in maintaining CNS homeostasis [372] and regulating barrier functions [367,378,379,380].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [367]
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“Accumulating evidence supports the active roles of BAMs in various brain pathologies owing to their anatomical characteristics: aligned between vascular walls and located at the interface between the brain parenchyma and peripheral immune system (Hawkes and McLaurin, 2009; Schläger et al., 2016; Faraco et al., 2017; P…”
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Ratzabi, A., Caspit, I. M., Telechi, I., Kim, J.-S., Vaknine, H., Blinder, P., Jung, S., & Stein, R. (2026) · Cell Death Discovery · doi:10.1038/s41420-026-03084-0 · Cited by 8
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Frontiers of Neurodegenerative Disease Treatment: Targeting Immune Cells in Brain Border Regions
Satyanarayanan, S. K., Han, Z., Xiao, J., Yuan, Q., Yung, W., Ke, Y., Chang, R. C., Zhu, M. H., Su, H., Su, K. P., et al. (2024) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2024.10.007 · Cited by 5
Human endogenous retroviruses: ammunition for myeloid cells in neurodegenerative diseases?
Gruchot, J., Kremer, D., & Küry, P. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.270311 · Cited by 5
“…are several specialized macrophage populations present at central nervous system interfaces such as the dura mater, the leptomeninges, the perivascular space and the choroid plexus (Kierdorf et al., 2019), it will be of interest to analyze their specific reactions to ENV production or stimulation.”
BackgroundBoucher, T., Liang, S., & Brown, A. M. (2022) · Journal of Leukocyte Biology · doi:10.1002/jlb.1mr0422-620r · Cited by 4
Intranasal route: The green corridor for Alzheimer's disease therapeutics
Chaudhury, S. S., Sinha, K., & Mukhopadhyay, C. D. (2021) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2021.102791 · Cited by 5
Perivascular SPP1 Mediates Microglial Engulfment of Synapses in Alzheimer’s Disease ModelsPreprint
Schepper, S. D., Ge, J. Z., Crowley, G., Ferreira, L. S. S., Garceau, D. T., Toomey, C. E., Sokolova, D., Childs, T., Lashley, T., Burden, J. J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.04.486547 · Cited by 5
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Spaceflight alters molecular networks linked to diverse human diseases in a single cellular model
Al‐Ahmadi, W., Barnawi, R., Hitti, E., & Khabar, K. S. A. (2026) · Science Advances · doi:10.1126/sciadv.adw7832 · Cited by 5
“This is because monocytes are precursors of macrophages that reside in many parts of the body and are crucial for maintaining tissue-specific homeostasis and functions ( 21 – 23 ).”
Leptomeningeal Neural Organoid Fusions as Models to Study Meninges-Brain Signaling
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Ferumoxytol-Enhanced MRI in Brain Tumor Imaging
Yağmurlu, B., Hamilton, B. E., Szidonya, L. K., Barajas, R., & Iv, M. (2024) · Advances in Clinical Radiology · doi:10.1016/j.yacr.2024.04.009 · Cited by 4
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“Peripheral macrophages alter their phenotype depending on the microenvironmental status: M1 polarization in which macrophages function as a pro-inflammatory driver versus M2 polarization in which macrophages function as an anti-inflammatory driver [20,21].”
BackgroundMacrophages clear the way for CNS fluid flow
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Not just Glia—Dissecting brain macrophages in the mouse
Frumer, G. R., Shin, S., Jung, S., & Kim, J. (2023) · Glia · doi:10.1002/glia.24445 · Cited by 3
“Besides the parenchymal microglia, the CNS also hosts BAM that have recently gained major attention (Kierdorf et al., 2019; Mildenberger et al., 2022; Munro et al., 2022; Rustenhoven & Kipnis, 2022) and are located in perivascular cuffs, the meninges, and the choroid plexus (Figure 1).”
BackgroundWang, A. Z., Bowman-Kirigin, J. A., Desai, R. R., Patel, P. R., Patel, B., Khan, S. M., Bender, D. E., Marlin, M. C., Liu, J., Osbun, J. W., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.08.03.454066 · Cited by 4
“BAMs have been described to play immune roles, such as support and 459 maintenance of barrier function and surveillance of antigens, within the meninges(62) and microglia have 460 been implicated in brain parenchyma homeostasis(63).”
BackgroundWITHDRAWN: Border-associated macrophages in the central nervous system
Sun, R., & Jiang, H. (2024) · Clinical Immunology · doi:10.1016/j.clim.2024.109921 · Cited by 4
RetractedMechanobiological Specialization of Choroid Plexus Macrophages Defined by Titin ExpressionPreprint
Bhatta, S., Grzybowski, A., Ortiz, G., & DiStasio, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.20.700716 · Cited by 6
“Like other BAMs, ChP macrophages exhibit specialized morphologies and dynamic pro-245 cesses shaped by the mechanical and biochemical attributes of their niche 37 .”
Kim, S., Joyce, L. R., Brady, A., Spencer, B. L., Pawlikowski, B. T., Derk, J., Doran, K. S., & Siegenthaler, J. A. (2026) · SSRN Electronic Journal · doi:10.64898/2026.03.04.709573 · Cited by 4
“…found in the meninges, choroid plexus, and perivascular spaces, and their activation has been implicated in various pathologies, including meningitis, ischemic stroke, Alzheimer’s disease, and multiple sclerosis (Kierdorf et al., 2019; Wang et al., 2023; Sun and Jiang, 2024; Van Hove et al., 2025).”
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“…exhibit a CD206+/CX3CR1-profile, and can be further subdivided into meningeal macrophages, perivascular macrophages (PVMs), and choroid plexus macrophages (CPMs) with distinct developmental origins (Utz et al., 2020; Goldmann et al., 2016; Kierdorf et al., 2019; Van Hove et al., 2019).”
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“Different from microglia in the brain parenchyma, these macrophages at the border of the central nervous system (CNS) are called CNS-or border-associated macrophages (CAMs or BAMs) [149–152].”
Common and distinct features of diverse macrophage populations in the central nervous system
Masuda, T. (2025) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.101.013 · Cited by 3
“21) For instance, in the TgCRND8 transgenic AD mouse model, depletion of pvMΦ by intraventricular injection of clodronate liposomes, a method that does not directly affect microglia or other CNS cells, resulted in a drastic increase in pathological A β deposition along the vasculature.”
Self-citationHunt, A. L., Khan, I., Wu, A. M. L., Makohon‐Moore, S. C., Hood, B. L., Conrads, K. A., Abulez, T. S., Ogata, J. D., Mitchell, D., Gist, G. D., et al. (2023) · Clinical & Experimental Metastasis · doi:10.1007/s10585-023-10233-7 · Cited by 3
“The normal brain is comprised of neurons, a protective blood–brain barrier, oligodendrocytes that produce myelin sheaths, astrocytes that connect neurons to the circulation, microglia, and blood-derived myeloid cells [49].”
Elucidation of the role of microglia‐macrophage‐based neuroinflammation in neurological diseases
Yamasaki, R. (2024) · Neurology and Clinical Neuroscience · doi:10.1111/ncn3.12829 · Cited by 3
SPION+ macrophage traffic out of the central nervous system with SIV infection
Alvarez, X. A., Wallis, Z. K., Midkiff, C. C., Mallard, J., Didier, P. J., & Williams, K. C. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02179-6 · Cited by 3
“These macrophages are a key component of the CNS immune defense but, when infected, can become reservoirs for SIV and HIV [3, 18, 21, 29, 35, 54].”
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“These differences likely reflect the distinct fluid-SPION interfaces in each anatomical compartment [18,60,61].”
Translational Interdisciplinary Science—Immune Cell Niches: Possible Targets for Stroke Therapy?
McCullough, L. D., & Moro, M. Á. (2021) · Stroke · doi:10.1161/strokeaha.121.033969 · Cited by 4
The Tabulae Paralytica: Multimodal single-cell and spatial atlases of spinal cord injuryPreprint
Skinnider, M. A., Gautier, M., Teo, A. Y. Y., Kathe, C., Hutson, T. H., Laskaratos, A., de Coucy, A., Regazzi, N., Aureli, V., James, N. D., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.23.544348 · Cited by 3
“Macrophages encom-passed border-associated macrophages (expressing H2-Aa ) that mediate immune responses in perivascular spaces 89 , as well as distinct inflammatory ( Ifi211 ), chemotaxis-inducing ( Cd300a ), and thrombospondin-sensing ( Htr2b ) subpopulations 58 .”
Background
Metadata
- Authors
- Kierdorf, K., Masuda, T., Jordão, M. J. C., & Prinz, M.
- Affiliations
- University of Freiburg (DE)
- Corresponding author
- Prinz, Marco
- Venue
- Nature Reviews Neuroscience
- Published
- 2019-07-29
- Volume
- 20
- Issue
- 9
- Pages
- 547-562
- ISSN
- 1471-003X (ISSN-L)
- 1471-0048
- OpenAlex
- W2965570118
- Semantic Scholar
- 7aa0033e693c776f7718f0c2d90733dadf1d5769
- Cited by
- 416
- References
- 196
- Citations by year
- 2026: 54 · 2025: 49 · 2024: 74 · 2023: 56 · 2022: 62 · 2021: 70 · 2020: 42 · 2019: 8
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature reviews. Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Keywords
- perivascular macrophages, choroid plexus macrophages, macrophage ontogeny, meninges, blood-brain barrier, neuroinflammation, neurodegenerative diseases
- MeSH terms
- Animals, Central Nervous System, Humans, Macrophages, Neurons, Inflammation Mediators, Neurodegenerative Diseases
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