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Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain
Open accessAbstract
The colony-stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microglia in the brain that originates from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within 1 week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin-positive cells that then differentiate into microglia.
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“In addition, it was reported that after inhibiting CSF-1R, the resident microglia display elevated proliferation and inflammation markers (64, 65)”
From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [65]
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“Tgfbr2 and Csf1r have also been demonstrated to play an essential signaling role in microglia development, where the absence of these genes or inhibition of their signaling shows marked reduction or complete absence of microglia”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Elmore et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Treatment with PLX is a highly effective and well tolerated strategy, with near complete elimination of microglia in the healthy brain after ~ 1 week. Cessation of PLX treatment is followed by a rapid (~ 1 week) rebound in microglia numbers.”
From Activated microglia drive demyelination via CSF1R signaling (2021) · cites this paper as Monica R. P. Elmore et al., 2014
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Withdrawal of PLX5622 treatment is known to result in a rapid and robust repopulation of microglia via self-renewal (28, 29)”
From Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection (2020) · cites this paper as [28]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“because these cytokines have been shown to play important roles in microglial proliferation and/or survival [43, 44].”
From IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia (2019) · cites this paper as [44]
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“the microglia population was found to be rapidly reconstituted by resident cells after genetic or pharmacological ablation of microglia (Bruttger et al., 2015; Elmore et al., 2014).”
From Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals (2025) · cites this paper as Elmore et al., 2014
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“Unlike non-plaque-associated (distal microglia; Extended Data Fig. 1b) or PU.1high plaque-associated microglia, this subpopulation appears independent of the activity of the essential microglial survival receptor CSF1R26,27 (Fig. 1d,e and Extended Data Fig. 1b–d).”
From Lymphoid gene expression supports neuroprotective microglia function (2025) · cites this paper as [26]
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In the citing paper
“Although previous studies identified the capacity of microglia to repopulate following experimental depletion in healthy13–15, aged17, irradiated18, or neurodegenerating brain19, we show that this feature can also serve to reinstate microglia after naturally occurring death following white matter injury, while regulating microglia activation.”
From Central nervous system regeneration is driven by microglia necroptosis and repopulation (2019) · cites this paper as [14]
In the citing paper
“Genetic defects in CSF1R and pharmacological blockade of CSF1R drastically reduce microglia numbers (5, 6).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [6]
In the citing paper
“evidence indicates that these cells interact with and modulate neuronal and synaptic elements, with direct effects on learning and memory [14], [15], [16], [17], [18], [19].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [14]
In the citing paper
“Microglia express and are critically dependent upon signaling through the myeloid CSF1/IL-34 receptor CSF1R for survival [14].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [14]
In the citing paper
“Microglial depletion also enhances performance in certain memory tasks [12, 14, 16] and prevents the forgetting of remote memories, and in association, the dissociation of memory engram cells in healthy adult mice [18].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [14]
In the citing paper
“Microglial CSF1R signalling is essential to their survival and has become a thoroughly tested and highly replicated model for targeted elimination of microglia (Elmore et al. , 2014; Asai et al. , 2015; Dagher et al. , 2015; Rice et al. , 2015; Acharya et al. , 2016; Feng et al. , 2016; Spangenberg et al. , 2016; Stafford et al. , 2016; Szalay et al. , 2016; Li et al. , 2017; Bennett et al. , 2018”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Elmore et al., 2014
In the citing paper
“Previously, we developed a pharmacological method to eliminate virtually all ( 99%) microglia from the murine brain for several months at a time (Elmore et al. , 2014; Dagher et al. , 2015), based on inhibition of colony-stimulating factor 1 receptor (CSF1Ri).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Elmore et al., 2014
In the citing paper
“As we previously demonstrated, microglia are critically dependent on CSF1R signaling for their survival17”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [17]
In the citing paper
“indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [17]
In the citing paper
“In vivo PLX5622 demonstrated desirable PK properties in mice, rats, dogs, and monkeys (Supplementary Table 5), with a brain penetrance of ~20% (compared to ~5% for PLX339717; Supplementary Table 6).”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [17]
In the citing paper
“In the MWM probe trial, PLX5622-treated wild-type mice tended to spend more time in the platform zone compared to wild-type mice (Fig. 3k), indicating that the long-term absence of microglia is not detrimental to murine cognitive function and may be beneficial, at least in this assay, which is consistent with our prior findings17,18.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [17]
In the citing paper
“While microglia can be indefinitely depleted via the continued administration of CSF1R inhibitors, the microglial compartment can also be repopulated upon CSF1R inhibitor withdrawal17,40,41.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [17]
In the citing paper
“We further examined the role of peripheral CSF1R inhibition on AD pathology by treating 1.5-month-old 5xFAD mice until 5 months of age with PLX3397 (75 ppm) chow (Fig. 7a) – a formulation that provides robust peripheral CSF1R inhibition without microglial elimination17.”
From Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model (2019) · cites this paper as [17]
In the citing paper
“Recent studies that have used an anti-CSF1R antibody187 and PLX3397 to block CSF1R suggest that inhibition of CSF1R causes the depletion of microglia188.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [188]
In the citing paper
“This report shows rapid repopulation of microglia following pharmacological depletion.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [188]
In the citing paper
“No sign of blood brain barrier (BBB) injury, as assessed by IgG penetration into the brain parenchyma was found similarly to earlier observations24.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“This regimen yields higher PLX3397 levels than that needed to maintain depletion of microglia24, but does not lead to microglia depletion.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“Absence of microglia did not lead to increased leukocyte recruitment to the brain 24 h (Fig. 1i) and 72 h (Supplementary Fig. 5) after cerebral ischaemia or inflammation as observed previously by others after hippocampal injury24.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“Since PLX3397 is quickly cleared from central and peripheral tissues24, the PLX3397 diet was withdrawn for 24 h after 21 days of microglia depletion in a separate group of animals, after which microglia remained fully depleted, but only trace amounts of the drug were detected in the brain24.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“High-dose treatment with a brain-penetrant CSF1R kinase inhibitor reversibly depletes microglia, an effect that has no apparent gross deleterious results in healthy mice, but that provides a powerful tool for inferring the various roles of microglia in more detail24.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“This is in line with previous observations using the same approach24, which also demonstrated a lack of illness and behavioural alterations in microglia-depleted animals2432.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“In addition, acute treatment with a PLX3397 dose higher than that needed to block microglial repopulation24 did not result in depletion of microglia and did not alter brain injury.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“In agreement with earlier results24, we have not found any obvious behavioural alterations, weight loss or sign of illness in mice fed a PLX3397 diet for 3 weeks or longer.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“In addition, acute treatment with a PLX3397 dose higher than that needed to block microglial repopulation24 did not result in depletion of microglia and did not alter brain injury.”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“withdrawal of PLX3397 for 24 h, which reduces drug concentrations to below detection level24”
From Microglia protect against brain injury and their selective elimination dysregulates neuronal network activity after stroke (2016) · cites this paper as [24]
In the citing paper
“indicating that elimination of EGFP+Iba1+ cells was due to programmed cell death of microglia as previously reported (Elmore et al., 2014)”
From Local cues establish and maintain region-specific phenotypes of basal ganglia microglia (2017) · cites this paper as Elmore et al., 2014
In the citing paper
“Microglia can be efficiently ablated in mice by chronic treatment with PLX5622 (PLX), a pharmacological inhibitor of the colony stimulating factor 1 receptor, CSF1R, which is required for microglia survival24.”
From Epigenetic regulation of brain region-specific microglia clearance activity (2018) · cites this paper as [24]
In the citing paper
“Pharmacological blockade of CSF1 receptors has been shown to impair microglial survival and can completely remove microglia from the mouse brain (53–55).”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [53]
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Metadata
- Authors
- Elmore, M. R. P., Najafi, A. R., Koike, M. A., Dagher, N. N., Spangenberg, E. E., Rice, R. A., Kitazawa, M., Matusow, B., Nguyen, H., West, B. L., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- University of California, Merced (US)
- Plexxikon (United States) (US)
- Corresponding author
- Green, Kim N.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 82
- Issue
- 2
- Pages
- 380-397
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4161285
- OpenAlex
- W2104431737
- Cited by
- 1,968
- References
- 46
- Citations by year
- 2026: 161 · 2025: 182 · 2024: 240 · 2023: 172 · 2022: 201 · 2021: 245 · 2020: 191 · 2019: 154 · 2018: 128 · 2017: 101 · 2016: 88 · 2015: 75 · 2014: 27
- FWCI
- 50.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1R01NS083801, F31NS086409, UL1 TR000153)
- Whitehall Foundation
- National Institute of Neurological Disorders and Stroke
- American Federation for Aging Research
- Alzheimer's Association (AG00538)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
- Keywords
- colony-stimulating factor 1 receptor, CSF1R signaling, microglia, CSF1R inhibitor, microglial depletion, microglial repopulation, nestin-positive cells, microglial proliferation, microglial differentiation, adult brain, microglial homeostasis, myeloid lineage
- MeSH terms
- Animals, Animals, Newborn, Brain, Enzyme Inhibitors, Gene Expression Regulation, Lipopolysaccharides, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Time Factors, Signal Transduction, Macrophage Colony-Stimulating Factor, Receptor, Macrophage Colony-Stimulating Factor, Cell Death, Microglia, Maze Learning, Cell Proliferation, Mice, Adult Stem Cells
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