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Microglia and Central Nervous System–Associated Macrophages—From Origin to Disease Modulation
Open accessAbstract
The immune system of the central nervous system (CNS) consists primarily of innate immune cells. These are highly specialized macrophages found either in the parenchyma, called microglia, or at the CNS interfaces, such as leptomeningeal, perivascular, and choroid plexus macrophages. While they were primarily thought of as phagocytes, their function extends well beyond simple removal of cell debris during development and diseases. Brain-resident innate immune cells were found to be plastic, long-lived, and host to an outstanding number of risk genes for multiple pathologies. As a result, they are now considered the most suitable targets for modulating CNS diseases. Additionally, recent single-cell technologies enhanced our molecular understanding of their origins, fates, interactomes, and functional cell statesduring health and perturbation. Here, we review the current state of our understanding and challenges of the myeloid cell biology in the CNS and treatment options for related diseases.
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Microglia are intricately involved in the development of the neuronal architecture of the embryonic brain by phagocytosing excess or apoptotic neuronal progenitor cells, while supporting the survival, proliferation, migration, and maturation of other NPCs and neurons.
“Microglia are intricately involved in the development of the neuronal architecture of the embryonic brain by phagocytosing excess or apoptotic neuronal progenitor cells (NPCs), while supporting the survival, proliferation, migration, and maturation of other NPCs and neurons ( Figure 1 Top) (13, 24).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [13]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredSingle-cell profiling suggested that CAMs share functions with microglia and astrocytes in maintaining CNS homeostasis and regulating barrier functions.
“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 [379]
The ‘CNS Macrophages as Tissue-Resident Immune Cells’ section says resident immune cells help maintain tissue homeostasis, and the ‘Functions of Microglia and CAMs During Development and Homeostasis’ section describes CAMs as possible regulators of immune responses at CNS borders. But our copy does not say that single-cell profiling identified functions CAMs share with both microglia and astrocytes, or that CAMs regulate barrier functions; it says CAM functions remain poorly understood. Page numbers were not available in the indexed passages. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPeripheral monocytes may infiltrate the brain and give rise to microglia-like cells, partially replacing resident microglia under pathological conditions.
“peripheral monocytes may infiltrate the brain and give rise to microglia-like cells, partially those that replace resident microglia under pathological conditions [37,38].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [37]
The Ontogeny and Fate of CNS Macrophages section describes blood- or bone marrow-derived cells engrafting after microglia were genetically depleted or functionally impaired, but does not establish partial replacement under pathological conditions generally. The Myeloid Cells in CNS Inflammation section specifically says that monocytes recruited during EAE do not contribute to the microglial compartment. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCHIP-derived myeloid cells can directly integrate into the central nervous system and may participate actively in neuroimmune processes relevant to AD pathogenesis.
“This presence confirms that CHIP-derived myeloid cells can directly integrate into the central nervous system and may participate actively in neuroimmune processes relevant to AD pathogenesis [10,37].”
From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [37]
The Ontogeny and Fate of CNS Macrophages section reports that blood- or bone-marrow-derived myeloid cells can engraft in the CNS, notably after irradiation or microglial depletion. The Myeloid Cells in CNS Inflammation section describes recruited monocytes contributing to inflammation in EAE. Neither passage identifies those cells as CHIP-derived or establishes their participation in Alzheimer’s disease pathogenesis. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMicroglial cells originate in the yolk sac and migrate to the developing brain at approximately the same time as neurons develop and before other glia appear.
“Microglial cells originate in the yolk sac and migrate to the developing brain at approximately the same time as the development of neurons is taking place, and before the appearance of other types of glia (13, 24).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [13]
Microglial cells perform a wide variety of functions, which demands a high degree of plasticity and adaptability.
“Microglial cells perform a wide variety of functions, which demands a high degree of plasticity and adaptability ( Figure 1 ) (13, 24, 25).”
From The role of microglia in multiple sclerosis: implications for treatment with Bruton’s tyrosine kinase inhibitors (2025) · cites this paper as [13]
Primary microglia isolated from brain of old mice feature increased expression of innate immune genes.
“Befitting their central role in shaping the immune state of the CNS26, primary microglia isolated from the brain of old mice featured a similar increase in the expression of innate immune genes (Fig. 3b).”
From cGAS–STING drives ageing-related inflammation and neurodegeneration (2023) · cites this paper as [26]
Microglia communicate with nearly all cell types in the brain to facilitate developmental process, maintain homeostasis, assist in tissue repair, and contribute to the pathogenesis of diseases.
“Microglia communicate with nearly all cell types in the brain to facilitate developmental process, maintain homeostasis, assist in tissue repair, and contribute to the pathogenesis of diseases.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [53]
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Metadata
- Authors
- Prinz, M., Masuda, T., Wheeler, M. A., & Quintana, F. J.
- Affiliations
- University of Freiburg (DE)
- Kyushu University (JP)
- Broad Institute (US)
- Corresponding author
- Prinz, Marco
- Masuda, Takahiro
- Wheeler, Michael A.
- Quintana, Francisco J.
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2021-04-26
- Volume
- 39
- Issue
- 1
- Pages
- 251-277
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- PMC
- PMC8085109
- OpenAlex
- W3127341444
- Cited by
- 584
- References
- 187
- Citations by year
- 2026: 102 · 2025: 127 · 2024: 129 · 2023: 104 · 2022: 87 · 2021: 35
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (20K22687)
- National Institute of Allergy and Infectious Diseases (R01AI126880)
- National Institute of Neurological Disorders and Stroke (F32NS101790, R01NS102807, K99NS114111, R00NS114111)
- National Institute of Environmental Health Sciences (R01ES029136)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, choroid plexus macrophages, perivascular macrophages, microglial plasticity, microglial heterogeneity, single-cell transcriptomics, neuroinflammation
- MeSH terms
- Animals, Brain, Central Nervous System, Humans, Macrophages, Microglia, Myeloid Cells
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